WO2017058754A1 - Combination therapy for treatment of hematological cancers and solid tumors - Google Patents

Combination therapy for treatment of hematological cancers and solid tumors Download PDF

Info

Publication number
WO2017058754A1
WO2017058754A1 PCT/US2016/053900 US2016053900W WO2017058754A1 WO 2017058754 A1 WO2017058754 A1 WO 2017058754A1 US 2016053900 W US2016053900 W US 2016053900W WO 2017058754 A1 WO2017058754 A1 WO 2017058754A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination therapy
administered
combination
inhibitor
days
Prior art date
Application number
PCT/US2016/053900
Other languages
French (fr)
Inventor
Stanley Frankel
Anita GANDHI
Original Assignee
Celgene Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Celgene Corporation filed Critical Celgene Corporation
Publication of WO2017058754A1 publication Critical patent/WO2017058754A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants

Definitions

  • combination therapies and methods for treating, preventing, and/or managing hematological cancers and solid tumors using combination therapies that include at least one immunomodulatory compound as described herein and at least one checkpoint inhibitor as described herein.
  • combination therapies that include at least one immunomodulatory compound as described herein and at least one checkpoint inhibitor as described herein.
  • a combination of at least one immunomodulatory compound and at least one checkpoint inhibitor for use in methods for treating, preventing, and/or managing hematological cancers and solid tumors.
  • Cancer can induce significant suppression of the immune system and escape from the immune surveillance mechanisms of the host. Dysregulation of host immune system is now considered one important hallmark of cancer (Hanahan et al, Cell, 2011, 144, 646-674). The interactions between cancer and the host immune system have been extensively studied and many types of immunotherapies have been explored for cancer treatment.
  • One class of immunotherapy is agents targeting specific checkpoint proteins that play critical roles in regulating T cell activation and proliferation. These proteins function as co- receptors on the surfaces of T cells and help regulate T cell responses following T cell activation (Wolchok et al., Cancer J, 2010, 16, 311-317).
  • Two of the best characterized checkpoint proteins are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1). Both serve as negative regulators of T cell activation.
  • CTLA-4 cytotoxic T-lymphocyte antigen 4
  • PD-1 programmed death-1
  • anti-CTLA-4 antibodies can directly activate CD4(+) and CD8(+) effector cells and generate antitumor responses (Wolchok et al., Oncologist, 2008, 13 (suppl 4), 2-9).
  • Pre-clinical models showed anti-tumor activity of anti-CTLA-4 antibodies in many tumor types, and a phase III randomized trial has demonstrated overall survival benefit of the anti-CTLA-4 antibody ipilimumab in patients with advanced melanoma (Hodi et al., N. Engl. J. Med., 2010, 363, 711- 723).
  • PD-1 signaling plays an important role in promoting regulatory T cell (Treg) function and preventing auto-immunity (Francisco et al, Immunol. Rev., 2010, 236, 219-242).
  • Tereg regulatory T cell
  • PD-L1 and PD-L2 Over-expression of PD-1 and its ligands, PD-L1 and PD-L2, has been found in many types of cancers and the over-expression was associated with advanced tumor stage and poor survival (Thompson et al, Cancer Res., 2006, 66, 3381-3385; Hamanishi et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 3360-3365).
  • Blocking of PD-l/PD-1 ligand interaction by antibodies can inhibit Treg function, promote host immune response, and inhibit tumor growth in various cancer models (Tsushima et al, Blood, 2007, 110, 180-185; Iwai et al, Proc. Natl. Acad. Sci. USA, 2002, 99, 12293-12997).
  • Early-phase clinical trials of anti-PD-1 antibodies have shown promising antitumor activity in solid cancers and hematological malignancies (Berger et al, Clin. Cancer Res., 2008, 14, 3044-3051; Ansell et al, N. Engl. J. Med, 2015, 372, 311-319).
  • unlike in solid tumors there is paucity of data and scientific knowledge of the role of check point inhibition in MDS.
  • combination therapies that include an
  • immunomodulatory compound as described herein and one or more checkpoint inhibitors.
  • the immunomodulatory compound is 3-(4-amino-l-oxo-l ,3- dihy dro-i soindol-2-yl)piperidine-2, 6-dione .
  • the immunomodulatory compound is 4-(amino)-2-(2,6-dioxo(3- piperidyl))-isoindoline-l,3-dione.
  • the checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1/PD-L1 inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a B7 inhibitor, a T- cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an OX40 (CD 134) agonist, a GITR agonist, a CD 137 agonist, a CD40 agonist, and an IDO inhibitor.
  • the checkpoint inhibitor comprises a CTLA-4 inhibitor.
  • the checkpoint inhibitor comprises tremelimumab or ipilimumab.
  • the checkpoint inhibitor comprises a PD-1 inhibitor.
  • the PD-1 inhibitor is selected from group consisting of nivolumab, pembrolizumab, CT-011, and AMP-224. In one embodiment the PD-1 inhibitor is nivolumab. In one embodiment the PD-1 inhibitor is pembrolizumab. In one embodiment the PD-1 inhibitor is CT-011. In one embodiment the PD-1 inhibitor is AMP-224.
  • the checkpoint inhibitor comprises a PD-L1 inhibitor.
  • the PD-L1 inhibitor selected from durvalumab or BMS-936559.
  • the PD-L1 inhibitor is durvalumab. In one embodiment the PD- Ll inhibitor is BMS-936559.
  • the checkpoint inhibitor comprises a PD-L2 inhibitor.
  • the checkpoint inhibitor comprises a LAG-3 inhibitor.
  • the LAG-3 inhibitor comprises IMP321 or BMS-986016.
  • the checkpoint inhibitor comprises a B7 inhibitor.
  • the checkpoint inhibitor comprises a B7-H3 inhibitor or a B7-H4 inhibitor.
  • the checkpoint inhibitor comprises T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor.
  • the checkpoint inhibitor comprises an OX40 (CD 134) agonist.
  • the OX40 agonist is selected from anti-OX-40 or MEDI6469.
  • the checkpoint inhibitor comprises GITR agonist.
  • the checkpoint inhibitor comprises CD137 agonist.
  • the CD137 agonist is selected from urelumab or PF-05082566.
  • the checkpoint inhibitor comprises CD40 agonist.
  • the checkpoint inhibitor comprises IDO inhibitor.
  • the IDO inhibitor is selected from INCB024360 or indoximod.
  • the combination also includes a secondary active agent as described herein.
  • the secondary active agent can be an antibody, such as for example rituximab, ibrutinib, or a combination of bendamustine/rituximab.
  • combination therapies that include a checkpoint inhibitor in combination with one or more secondary active agents.
  • the combination therapy includes a PD-L1 inhibitor described herein in combination with one or more secondary active agents.
  • the PD-L1 inhibitor is durvalumab.
  • the secondary active agent is ibrutinib. In one embodiment, the secondary active agent is rituximab. In one embodiment the secondary active agent is bendamustine. In one embodiment the secondary active agent is a combination of rituximab and bendamustine.
  • [0037] is a method of treating, preventing, and/or managing solid tumors by administering to a patient in need thereof the combination therapy as described herein.
  • the solid tumor comprises cancer of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, or uterus.
  • the patient was treated with a prior treatment comprising a hypomethylating agent (HMA).
  • HMA hypomethylating agent
  • the patient was treated with one or more of a proteasome inhibitor, an immunomodulatory agent, a histone deacetylase inhibitor (HDAC inhibitor) or an alkylating agent; or a combination thereof.
  • a proteasome inhibitor an immunomodulatory agent, a histone deacetylase inhibitor (HDAC inhibitor) or an alkylating agent; or a combination thereof.
  • HDAC inhibitor histone deacetylase inhibitor
  • the patient has previously received stem cell transplantion.
  • the stem cell transplantion is an autologous stem cell transplant.
  • the stem cell transplantion is allogeneic.
  • the stem cell transplantation comprises hematopoietic stem cell transplant, or peripheral blood stem cell transplant.
  • the patient has not previously received stem cell transplantation.
  • the combination therapy reduces or eliminates minimal residual disease (MRD) state in said patient.
  • MRD minimal residual disease
  • the combination therapy is administered after administration of chemotherapy. In one embodiment the combination therapy is administered before or during administration of chemotherapy.
  • [0045] in another aspect is a method of treating, preventing, and/or managing hematological cancer by administering to a patient in need thereof the combination therapy as described herein.
  • the hematological cancer is, non-Hodgkin's lymphoma (NHL), Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) B-cell lymphoma, MALT, lymhoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, adult T-cell lymphoma, Peripheral T-cell lymphoma, other B and T cell lymphoma/leukemias, and multiple myeloma.
  • NHL non-Hodgkin's lymphoma
  • HL Hodgkin lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MZL marginal zone lymphoma
  • MCL man
  • the hematological cancer is chronic lymphocytic leukemia.
  • the patient has hematological cancer that is relapsed or refractory. In one embodiment the patient has cancer that is relapsed or refractory.
  • the patient was treated with a prior treatment comprising a hypomethylating agent (HMA).
  • HMA hypomethylating agent
  • the combination therapy reduces or eliminates minimal residual disease (MRD) state in the patient.
  • MRD minimal residual disease
  • the combination therapy is administered after administration of chemotherapy.
  • MDS myelodysplastic syndromes
  • AML acute myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • the MDS is high risk MDS.
  • the AML is relapsed/refractory AML, trilineage dysplasia AML (AML-TLD), or therapy induced AML (tAML).
  • AML-TLD trilineage dysplasia AML
  • tAML therapy induced AML
  • the patient has MDS that is relapsed or refractory.
  • the patient was treating with a prior treatment comprising a hypomethylating agent (HMA).
  • HMA hypomethylating agent
  • the combination therapy includes a compound described herein, a checkpoint inhibitor described herein, and optionally one or more secondary active agents described herein.
  • the combination therapy includes a checkpoint inhibitor as described herein in combination with one or more secondary active agents described herein.
  • the combination therapy includes a secondary active agent as described herein and reduces or eliminates minimal residual disease (MRD) state in said patient.
  • MRD minimal residual disease
  • the combination therapy includes a secondary active agent as described herein and the combination is administered after administration of a previous chemotherapy.
  • the combination therapy is administered before or after a stem cell transplant (SCT).
  • SCT stem cell transplant
  • the combination therapy is administered within 180 days of a SCT.
  • the combination therapy is administered after a donor lymphocyte infusion (DLI).
  • DLI donor lymphocyte infusion
  • the administration of a combination therapy described herein reduces or eliminates the need for immunosuppressive drugs.
  • the combination therapy prolongs complete remission of said MDS compared to treatment without said combination therapy.
  • the immunomodulatory compound of said combination therapy is administered daily for 21 consecutive days followed by a 7 day rest period in a 28 days cycle.
  • the checkpoint inhibitor is administered on one or more days in a 28 days cycle.
  • the checkpoint inhibitor is administered on day 1 of a 28 day cycle.
  • the checkpoint inhibitor is administered on day 1 of cycles 1 through 13.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is an anti-PD-Ll antibody.
  • the anti-PD-Ll antibody comprises durvalumab.
  • the 28 days cycle is repeated 1-12 times.
  • the combination therapy is administered to said patient until disease progression or unacceptable toxicity.
  • the method further comprises administering a secondary active agent.
  • the secondary active agent is administered weekly in a 28 days cycle. In one embodiment, administration of the secondary active agent is continuous without a rest period. In one embodiment, administration of the secondary active agent is stopped during a 7-day rest period in the cycle.
  • the secondary active agent is rituximab.
  • the immunomodulatory compound of said combination therapy is administered at an amount of about 0.5 to about 5 mg.
  • the immunomodulatory compound of said combination therapy is administered at an amount of about 1 to about 5 mg. [0081] In one embodiment the immunomodulatory compound of said combination therapy is administered at an amount of about 1 to about 25 mg.
  • the immunomodulatory compound of said combination therapy is administered at an amount of about 5 to about 25 mg.
  • the immunomodulatory compound is administered at about 10 mg or about 20 mg.
  • the checkpoint inhibitor is administered at an amount of about 500 mg to about 2000 mg.
  • the checkpoint inhibitor is administered at an amount of about 1500 mg.
  • the patient has been previously treated for cancer. In one embodiment the patient has not been previously treated for cancer.
  • the patient is non-responsive to at least one anti-cancer treatment.
  • the patient has a cancer that is resistance to at least one anticancer treatment.
  • the patient has undergone at least one surgery to treat said cancer.
  • HCC hepatocellular carcinoma
  • the B-cell malignancy is selected from the group consisting of mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B- cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), and modular lymphocyte pre-dominant Hodgkin lymphoma.
  • the B-cell malignancy is mantle cell lymphoma (MCL).
  • the B-cell malignancy is follicular lymphoma (FL). In one embodiment, the B-cell malignancy is chronic lymphocytic leukemia (CLL). In one embodiment, the B-cell malignancy is Burkitt lymphoma. In one embodiment, the B-cell malignancy is marginal-zone lymphoma (MZL) including splenic variants. In one embodiment, the B-cell malignancy is diffuse large B- cell lymphoma (DLBCL). In one embodiment, the B-cell malignancy is lymphoplasmacytic lymphoma (LPL). In one embodiment, the B-cell malignancy is multiple myeloma (MM).
  • FL follicular lymphoma
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL). In one embodiment, the B-cell malignancy is Burkitt lymphoma. In one embodiment, the B-cell malignancy is marginal-zone lymphoma (MZL) including splenic variants
  • the B-cell malignancy is classical type Hodgkin lymphoma (HL). In one embodiment, the B-cell malignancy is modular lymphocyte pre-dominant Hodgkin lymphoma. In one embodiment, the B-cell malignancy is multiple myeloma.
  • the T-cell malignancy is selected from the group consisting of peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, angioimunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, lymphoblastic lymphoma, treatment related T-cell lymphoma; T-cell NHL, or chronic T-cell lymphoma.
  • the T-cell malignancy is peripheral T-cell lymphoma (not otherwise specified).
  • the T-cell malignancy is analplastic large cell lymphoma. In one embodiment, the T-cell malignancy is Sezary syndrome. In one embodiment, the T-cell malignancy is primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. In one embodiment, the T-cell malignancy is angioimunoblastic lymphoma. In one embodiment, the T-cell malignancy is cutaneous T-cell lymphoma. In one embodiment, the T-cell malignancy is adult T-cell leukemia/lymphoma (ATLL). In one embodiment, the T-cell malignancy is blastic NK-cell lymphoma. In one embodiment, the T-cell malignancy is lymphoblastic lymphoma.
  • ATLL adult T-cell leukemia/lymphoma
  • the T-cell malignancy is treatment related T-cell lymphoma. In one embodiment, the T-cell malignancy is T-cell NHL. In one embodiment, the T-cell malignancy is chronic T-cell lymphoma. [0096] In another aspect is a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
  • lymphoma in another aspect is a method for treating lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
  • NDL non-Hodgkin lymphoma
  • the combination includes administering a secondary active agent as described herein.
  • the secondary active agent is rituximab, ibrutinib, or a
  • [00101] in another aspect is a method for treating locally advanced or metastatic transitional cell bladder cancer in a patient in need thereof, said method comprising administering a combination therapy as described herein in combination with gemcitabine and cisplatinum.
  • a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
  • lymphoma in another aspect is a method for treating lymphoma as described herein comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
  • [00104] in another aspect is a method for treating pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma, said method comprising administering to said pediatric patient a combination therapy as described herein in combination with
  • a method for treating relapsed or progressive CNS cancer comprising administering a combination therapy as described herein in combination with celecoxib, etoposide and cyclophosphamide.
  • a method for treating patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms said method comprising
  • [00107] in another aspect is a method for treating patients with recurrent glioblastoma, said method comprising administering a combination therapy as described herein in combination with irinotecan.
  • [00108] in another aspect is a method for treating pediatric patients with brain stem glioma, said method comprising administering a combination therapy as described herein in combination with carboplatin.
  • [00109] in another aspect is a method for treating pediatric patients with progressive malignant gliomas, said method comprising administering a combination therapy as described herein in combination with procarbazine.
  • [00110] in another aspect is a method for treating patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms , said method comprising administering a combination therapy as described herein in combination with cyclophosphamide.
  • [00111] in another aspect is a method for treating high grade recurrent malignant gliomas, said method comprising administering a combination therapy as described herein in combination with Gliadel®.
  • [00112] in another aspect is a method for treating anaplastic astrocytoma, said method comprising administering a combination therapy as described herein in combination with temozolomide and tamoxifen.
  • gliomas In another aspect is a method for treating gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma, said method comprising administering a combination therapy as described herein in combination with topotecan.
  • [00114] in another aspect is a method for treating patients with metastatic breast cancer, said method comprising administering a combination therapy as described herein in combination with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, or PLX3397 (Plexxikon); or a combination thereof.
  • [00115] in another aspect is a method for treating neuroendocrine tumors, said method comprising administering a combination therapy as described herein in combination with temozolomide.
  • [00116] in another aspect is a method for treating patients with recurrent or metastatic head or neck cancer, said method comprising administering a combination therapy as described herein in combination with gemcitabine.
  • [00118] in another aspect is a method for treating patients with colon cancer, said method comprising administering a combination therapy as described herein in combination ARISA®, avastatin, taxol, and/or taxotere.
  • a method for treating patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma comprising administering a combination therapy of any one of claims 1 in combination with capecitabine and/or PLX4032 (Plexxikon).
  • [00120] in another aspect is a method for treating refractory colorectal cancer, said method comprising administering a combination therapy as described herein in combination with capecitabine, xeloda, and/or CPT-11.
  • [00121] in another aspect is a method for treating patients with refractory colorectal cancer or patients with unresectable or metastatic colorectal carcinoma, said method comprising administering a combination therapy as described herein in combination with capecitabine and irinotecan.
  • a method for treating patients with unresectable or metastatic hepatocellular carcinoma comprising administering a combination therapy as described herein in combination with interferon alpha or capecitabin.
  • a method for treating patients with primary or metastatic liver cancer comprising administering a combination therapy as described herein in combination with cisplatin and thiotepa.
  • [00124] in another aspect is a method for treating patients with refractory or relapsed or high- risk acute myelogenous leukemia, said method comprising administering a combination therapy as described herein in combination with fludarabine, carboplatin, and/or topotecan.
  • [00125] in another aspect is a method for treating patients with unfavorable karotype acute myeloblastic leukemia, said method comprising administering a combination therapy as described herein in combination with liposomal daunorubicin, topotecan and/or cytarabine.
  • a method for treating patients with non-small cell lung cancer comprising administering a combination therapy as described herein in combination with gemcitabine, abraxane, erlotinib, geftinib, and/or irinotecan.
  • [00127] in another aspect is a method for treating patients with non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with carboplatin and irinotecan.
  • [00128] in another aspect is a method for treating patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy, said method comprising administering a combination therapy as described herein in combination with doxetaxol.
  • a method for treating patients with non-small cell lung cancer comprising administering a combination therapy as described herein in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy.
  • [00130] in another aspect is a method for treating patients with stage MB or IV non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with taxotere.
  • a method for treating patients with small cell lung cancer comprising administering a combination therapy as described herein in combination with oblimersen.
  • a method for treating patients with lymphoma and other blood cancers comprising administering a combination therapy as described herein in combination with ABT-737 and/or obatoclax.
  • [00133] in another aspect is a method for treating patients with various types of lymphoma, said method comprising administering a combination therapy as described herein in combination with vinblastine or fludarabin.
  • a method for treating patients with Hodgkin's lymphoma, non- Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma comprising administering a combination therapy as described herein.
  • [00135] in another aspect is a method for treating patients with melanoma, said method comprising administering a combination therapy as described herein in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine.
  • [00136] in another aspect is a method for treating patients with malignant mesothelioma, or stage MB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome, said method comprising administering a combination therapy as described herein in combination with vinorelbine.
  • a method for treating multiple myeloma comprising administering a combination therapy as described herein in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
  • cyclophosphamide IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, a proteasome inhibitor, or a combination thereof.
  • the method is a method of treating patients having relapsed or refractory multiple myeloma by administering a combination therapy described herein in combination with dexamethasone.
  • a method for treating patients with ovarian cancer comprising administering a combination therapy as described herein in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
  • [00140] in another aspect is a method for treating patients with prostate cancer, said method comprising administering a combination therapy as described herein in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine,
  • dexamethasone GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon, or a combination thereof.
  • [00141] in another aspect is a method for treating patients with renal cell cancer, said method comprising administering a combination therapy as described herein in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
  • a method for treating patients with gynecologic, uterus or soft tissue sarcoma cancer comprising administering a combination therapy as described herein in combination with IFN, a COX-2 inhibitoror, sulindac, or a combination thereof.
  • a method for treating patients with a solid tumor comprising administering a combination therapy as described herein in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
  • a method for treating patients with scleroderma or cutaneous vasculitis comprising administering a combination therapy as described herein in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
  • administer refers to the act physically delivering a substance as it exists outside the body into a patient, such as by oral, mucosal, intradermal, intravenous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art.
  • administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.
  • a subject can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkey and human).
  • the subject is a human.
  • the subject is a mammal (e.g., a human) having a disease, disorder or condition described herein.
  • the subject is a mammal (e.g., a human) at risk of developing a disease, disorder or condition described herein.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Hematological cancer refers to blood-borne tumors (e.g., multiple myeloma, lymphoma and leukemia).
  • Tumor and solid tumor refer to all lesions and neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. Other exemplary cancers are provided elsewhere herein.
  • Neoplastic refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth.
  • Multiple myeloma or “MM” is a cancer of plasma cells in the bone marrow.
  • M-protein short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by the myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.
  • Skeletal symptoms including bone pain, are among the most clinically significant symptoms of multiple myeloma.
  • Malignant plasma cells release osteoclast stimulating factors (including IL-1, IL-6 and TNF) which cause calcium to be leached from bones causing lytic lesions; hypercalcemia is another symptom.
  • the osteoclast stimulating factors also referred to as cytokines, may prevent apoptosis, or death of myeloma cells.
  • cytokines also referred to as cytokines
  • Other common clinical symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.
  • An improvement in the cancer or cancer-related disease can be characterized as a complete or partial response.
  • “Complete response” or “CR” refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements.
  • “Partial response” refers to at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions.
  • a "sarcoma” is a solid tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Exemplary sarcomas that can be treated, prevented, and/or managed using the compositions and methods described herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma
  • a "carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • Exemplary carcinomas that can be treated with the compositions and methods described herein include, adenocarcimonas, colorectal carcinoma, colorectal adenocarcinoma, acinar carcinoma, lung carcinoma, alveolar cell carcinoma, basal cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, chorionic carcinoma, colloid carcinoma, corpus carcinoma, cribriform carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lymphoepithelial carcinoma, nasophary
  • treat refers to an action that occurs while a patient has a disease, disorder or condition described herein.
  • Treat also refer to the reduction or amelioration of the progression, severity, and/or duration of a disease, disorder or condition described herein resulting from the administration of one or more therapies.
  • refractory or resistant refers to a circumstance where patients, even after intensive treatment, have residual cancer cells (e.g., leukemia or lymphoma cells) in their lymphatic system, blood and/or blood forming tissues (e.g., marrow).
  • residual cancer cells e.g., leukemia or lymphoma cells
  • blood and/or blood forming tissues e.g., marrow
  • the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. In certain cases, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder. In certain embodiments, a subject is administered one or more therapies to "manage” a disease, disorder or condition, or one or more symptoms thereof, so as to prevent the progression or worsening of the disease, disorder or condition.
  • the term "preventing” refers to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of cancer and/or other disorders described herein.
  • prevention includes the inhibition or reduction of a symptom of the particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term “prevention” may be interchangeably used with the term “prophylactic treatment.”
  • a prophylactically effective amount of a compound is an amount sufficient to inhibit or reduce a symptom of a disease or to prevent recurrence of a disease.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the inhibition or reduction of a symptom of a disease or recurrence of a disease.
  • the term "prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term "effective amount” as used herein refers to the amount of a therapy (e.g., a composition provided herein) which is sufficient to reduce and/or ameliorate the severity and/or duration of a given disease, disorder or condition and/or a symptom related thereto. This term also encompasses an amount necessary for the reduction or amelioration of the advancement or progression of a given disease, disorder or condition, reduction or amelioration of the recurrence, development or onset of a given disease, disorder or condition, and/or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy. In some embodiments, "effective amount” as used herein also refers to the amount of therapy provided herein to achieve a specified result.
  • the term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a cancer, or to delay or minimize one or more symptoms associated with the presence of the cancer.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the cancer.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of cancer, or enhances the therapeutic efficacy of another therapeutic agent.
  • the term “therapy” refers to any protocol, method and/or agent that can be used in the prevention, management, treatment and/or amelioration of a given disease, disorder or condition.
  • the terms “therapies” and “therapy” refer to a drug therapy, biological therapy, supportive therapy, and/or other therapies useful in the prevention, management, treatment and/or amelioration of a given disease, disorder or condition known to one of skill in the art such as medical personnel.
  • pharmaceutically acceptable means being approved by a regulatory agency of the Federal or state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic,
  • suitable are hydrochloric, hydrobromic, phosphoric, and sulfuric acids.
  • immunomodulatory compound refers generally to a molecule or agent capable of altering the immune response in some way.
  • immunomodulatory agent refers generally to a molecule or agent capable of altering the immune response in some way.
  • compound refers generally to a molecule or agent capable of altering the immune response in some way.
  • immunomodulatory compounds include those disclosed in Section 5.2.1 below.
  • stereoisomer encompasses all enantiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds provided herein.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • stereomerically enriched means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70%) by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • the term “enantiomerically pure” means a stereomerically pure composition of a compound having one chiral center.
  • enantiomerically enriched means a stereomerically enriched composition of a compound having one chiral center.
  • antibody means a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen.
  • Antibodies provided herein include, but are not limited to, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies, antibody mimetics, chimeric antibodies, humanized antibodies, human antibodies, antibody fusions, antibody conjugates, single chain antibodies, antibody derivatives, antibody analogues and fragments thereof, respectively. Also included are immunological fragments of an antibody (e.g., a Fab, a Fab', a F(ab') 2 , or a scFv), irrespective of whether such antibodies are produced, in whole or in part, via immunization, through recombinant technology, by way of in vitro synthetic means, or otherwise.
  • an antibody e.g., a Fab, a Fab', a F(ab') 2 , or a scFv
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%,40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • Combination therapies described herein can include one or more immunomodulatory compounds and one or more checkpoint inhibitors (CPIs). In other embodiments, combination therapies described herein include one or more CPIs in combination with one or more secondary active agents. Also provided herein are combinations of at least one immunomodulatory compound and at least one checkpoint inhibitor for use in a method of treatment, prevention, and management of cancer - particularly hematological cancers and solid tumors as described herein.
  • the immunomodulatory agent is lenalidomide.
  • Lenalidomide has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma (MM) in combination with dexamethasone; transfusion-dependent anemia due to low- or intermediate- 1 -risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities; and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
  • FDA U.S. Food and Drug Administration
  • MDS low- or intermediate- 1 -risk myelodysplastic syndromes
  • MCL mantle cell lymphoma
  • the immunomodulatory agent is Pomalidomide.
  • Pomalidomide is currently approved by the FDA for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
  • the inflammatory cytokine TNF-a which is produced by macrophages and monocytes during acute inflammation, causes a diverse range of signaling events within cells. Without being limited by a particular theory, one of the biological effects exerted by the immunomodulatory compounds disclosed herein can be the reduction of myeloid cell TNF-a production. Immunomodulatory compounds disclosed herein may enhance the degradation of TNF-a mRNA.
  • immunomodulatory compounds disclosed herein may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds disclosed herein may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds may have anti-inflammatory properties against myeloid cell responses, yet efficiently co-stimulate T cells to produce greater amounts of IL-2, IFN- ⁇ , and to enhance T cell proliferation and CD8+ T cell cytotoxic activity.
  • immunomodulatory compounds disclosed herein may be capable of acting both indirectly through cytokine activation and directly on Natural Killer (“NK”) cells and Natural Killer T (“NKT”) cells, and increase the NK cells' ability to produce beneficial cytokines such as, but not limited to, IFN- ⁇ , and to enhance NK and NKT cell cytotoxic activity.
  • NK Natural Killer
  • NKT Natural Killer T
  • the immunomodulatory compounds disclosed herein contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers.
  • stereomerically pure forms of the immunomodulatory compounds as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds may be used.
  • isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33 :2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds
  • Immunomodulatory compounds include, but are not limited to, 1- oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Patent no. 5,635,517 which is incorporated herein by reference. These compounds have the structure I:
  • immunomodulatory compounds of formula I include, but are not limited to:
  • the immunomodulatory agents described herein include pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereiosmers thereof.
  • the immunomodulatory agents described herein include pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereiosmers thereof.
  • immunomodulatory agents described herein include pharmaceutically acceptable salts thereof. In one embodiment, the immunomodulatory agents described herein do not include
  • Such compounds can be obtained via standard, synthetic methods (see e.g., United States Patent No. 5,635,517, incorporated herein by reference). The compounds are also available from Celgene Corporation, Warren, NJ.
  • Immunomodulatory agents include but are not limited to pomalidomide and lenalidomide.
  • Lenalidomide has the following structure:
  • the compound is amorphous 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione.
  • the compound is srystalline solid form of 3-(4-amino-l-oxo-l ,3-dihydro- isoindol-2-yl)piperidine-2,6-dione, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, or Form H (see U.S. Patent No. 7,465,800 incorporated herein by reference).
  • the immunomodulatory agent is lenalidomide and not a pharmaceutically acceptable salt thereof.
  • the immunomodulatory agent is a hydrate of lenalidomide.
  • Lenalidomide can be prepared as described in WO2012/ 149299, the disclosure of which is incorporated herein by reference in its entirety.
  • the compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
  • Lenalidomide can be prepared as described in WO2012/ 149299, the disclosure of which is incorporated herein by reference in its entirety.
  • the compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
  • Pomalidomide has the following structure:
  • the immunomodulatory agent is a hydrate of pomalidomide.
  • the compounds described herein may be small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides,
  • Combination therapies described herein include one or more checkpoint inhibitor(s) optionally administered in combination with compounds described herein in connection with methods provided herein.
  • combination therapies described herein include one checkpoint inhibitor administered in combination with a compound described herein.
  • combination therapies described herein include two checkpoint inhibitors administered in combination with a compound described herein.
  • combination therapies described herein include three or more checkpoint inhibitors administered in combination with a compound described herein in connection with methods provided herein.
  • combination therapies described herein include one checkpoint inhibitor described herein administered in combination with two compounds described herein.
  • combination therapies described herein include one checkpoint inhibitor administered in combination with one or more secondary active agents described herein.
  • combination therapies described herein include lenalidomide or pomalidomide administered in combination with one or more checkpoint inhibitors.
  • immune checkpoint inhibitor refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
  • checkpoint proteins regulate T-cell activation or function.
  • Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 72, 252-264). These proteins appear responsible for co-stimulatory or inhibitory interactions of T-cell responses.
  • Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses.
  • Immune checkpoint inhibitors include antibodies or are derived from antibodies.
  • the checkpoint inhibitor is a CTLA-4 inhibitor.
  • the CTLA-4 inhibitor is an anti-CTLA-4 antibody.
  • anti-CTLA-4 antibodies include, but are not limited to, those described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207, 157; 6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein in their entireties.
  • the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206).
  • the anti- CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101).
  • Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name YervoyTM.
  • combination therapies that include one or more CTLA-4 inhibitors and a compound as described herein.
  • the combination therapy includes tremelimumab (ticilimumab or CP-675,206) and a compound as described herein.
  • the combination therapy can include ipilimumab (MDX-010 or MDX-101) and a compound as described herein.
  • Such combination therapies can include CTLA-4 inhibitors and compounds described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a CTLA-4 inhibitor include those as set forth herein, including for example lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a PD-1/PD-L1 inhibitor.
  • PD-1/PD-L1 inhibitors include, but are not limited to, those described in US Patent Nos.
  • the checkpoint inhibitor is a PD-1 inhibitor.
  • the PD-1 inhibitor is an anti-PD-1 antibody.
  • the anti-PD-1 antibody is nivolumab (also known as ONO-4538, BMS-936558, or MDX1106) or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab).
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name OpdivoTM.
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name KeytrudaTM.
  • the anti-PD-1 antibody is CT- 011, a humanized antibody. CT-011 administered alone has failed to show response in treating AML at relapse.
  • the anti-PD-1 antibody is AMP -224, a fusion protein. [00193] Accordingly, provided herein are combination therapies that include a PD-1 inhibitor and a compound as described herein. In one embodiment is a combination therapy that includes an anti-PD-1 antibody and a compound as described herein.
  • a combination therapy that includes nivolumab (ONO-4538, BMS-936558, and MDXl 106) and a compound as described herein.
  • a combination therapy that includes pembrolizumab and a compound as described herein.
  • a combination therapy that includes CT-011 and a compound as described herein.
  • a combination therapy that includes AMP-224 and a compound as described herein.
  • Compounds useful in combination therapies including a PD-1 inhibitor or antibody include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is an anti-PD-Ll antibody.
  • the anti-PD-Ll antibody is durvalumab (MEDI4736).
  • the anti-PD-Ll antibody is BMS-936559 (also known as MDX-1105-01).
  • combination therapies that include a PD-L1 inhibitor and a compound as described herein.
  • a combination therapy that includes durvalumab and a compound as described herein.
  • Such embodiments include PD-L1 inhibitors and compounds as described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a PD-L1 inhibitor include, but are not limited to, lenalidomide or pomalidomide.
  • the combination includes a PD-L1 antibody such as durvalumab and a compound described herein such as lenalidomide or pomalidomide.
  • the combination includes a PD-L1 antibody such as durvalumab in combination with one or more secondary active agents described herein.
  • the checkpoint inhibitor is a PD-L2 inhibitor.
  • the PD-L2 inhibitor is an anti-PD-L2 antibody.
  • the anti-PD- L2 antibody is rHIgM12B7A.
  • embodiment is a combination therapy that includes rHIgM12B7A and a compound as described herein.
  • Such embodiments include PD-L2 inhibitors and compounds as described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a PD-L2 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor.
  • the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al, J. Immunol, 2007, 179, 4202-4211).
  • the LAG- 3 inhibitor is BMS-986016.
  • combination therapies that include a LAG- 3 inhibitor as described herein and a compound as described herein.
  • a combination therapy that includes IMP321 and a compound as described herein.
  • Such embodiments include LAG-3 inhibitors and compounds as described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a LAG-3 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitors is a B7 inhibitor.
  • the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor.
  • the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).
  • combination therapies that include a B7 inhibitor and a compound described herein.
  • a combination therapy that includes B7-H3 inhibitor as described herein and a compound as described herein.
  • a combination therapy that includes a B7-H4 inhibitor as described herein and a compound as described herein.
  • a combination therapy that includes MGA271 and a compound as described herein.
  • Such embodiments include a B7 inhibitor as described herein and a compound as described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a B7 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitors is a TIM-3 (T-cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86;
  • a combination therapy that includes a TIM-3 inhibitor and a compound as described herein, at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a TIM-3 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is an OX40 (CD 134) agonist.
  • the checkpoint inhibitor is an anti-OX40 antibody.
  • the anti- OX40 antibody is anti-OX-40.
  • the anti-OX40 antibody is MEDI6469. Accordingly, in one embodiment is a combination therapy that includes an OX40 agonist and a compound as described herein. In another embodiment is a combination therapy that includes an anti-OX40 antibody and a compound a described herein. In still another embodiment is a combination therapy that includes anti-OX-40 and a compound as described herein. In yet another embodiment is a combination therapy that includes MEDI6469 and a compound as described herein.
  • Such embodiments include OX40 agonists and compounds, as described herein, at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including an OX40 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a GITR agonist.
  • the checkpoint inhibitor is an anti-GITR antibody.
  • the anti- GITR antibody is TRX518.
  • combination therapies that include a GITR agonist and a compound as described herein.
  • a combination therapy that includes an anti-GITR antibody and a compound as described herein.
  • a combination therapy that includes TRX518 and a compound as described herein.
  • Such embodiments include GITR agonists and compounds, as described herein, at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a GITR inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a CD137 agonist.
  • the checkpoint inhibitor is an anti-CD137 antibody.
  • the anti- CD137 antibody is urelumab.
  • the anti-CD137 antibody is PF-05082566.
  • combination therapies that include a CD137 agonist and a compound as described herein.
  • a combination therapy that includes an anti-CD 137 antibody and a compound as described herein.
  • a combination therapy that includes urelumab and a compound as described herein.
  • Such embodiments include CD137 agonists and compounds, as described herein, at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a CD 137 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is a CD40 agonist.
  • the checkpoint inhibitor is an anti-CD40 antibody.
  • the anti-CD40 antibody is CF-870,893.
  • combination therapies that include a CD40 agonist and a compound as described herein.
  • a combination therapy that includes an anti-CD40 antibody and a compound as described herein.
  • a combination therapy that includes CF-870,893 and a compound as described herein.
  • Such embodiments include CD40 agonists and compounds, as described herein, at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a CD40 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).
  • rhIL-15 recombinant human interleukin-15
  • a combination therapy that includes rhIL-15 and a compound as described herein at concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including a rhIL-15 include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • the checkpoint inhibitor is an IDO inhibitor.
  • the IDO inhibitor is INCB024360.
  • the IDO inhibitor is indoximod.
  • combination therapies that include an IDO inhibitor as described herein and a compound as described herein.
  • a combination therapy that includes INCB024360 and a compound as described herein.
  • a combination therapy that includes indoximod and a compound as described herein.
  • Such embodiments include an IDO inhibitor and a compound, as described herein, in concentrations and amounts as set forth herein.
  • Compounds useful in combination therapies including an IDO inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
  • combination therapies include lenalidomide and/or pomalidomide as described herein at concentrations and amounts as set forth herein.
  • combination therapies as described herein can include two or more of the checkpoint inhibitors described herein (including checkpoint inhibitors of the same or different class).
  • the combination therapies described herein can be used in combination with secondary active agents as described herein where appropriate for treating diseases described herein and understood in the art.
  • a first therapy e.g., a compound as described herein
  • a second therapy e.g., a checkpoint inhibitor as described herein
  • a first therapy e.g., a checkpoint inhibitor as described herein
  • a second therapy e.g., a compound as described herein
  • a CPI as described herein can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a secondary active agent as described herein to the subject.
  • a secondary active agent as described herein to the subject.
  • a secondary active agent as described herein can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a CPI (e.g. durvalumab) as described herein to the subject.
  • a CPI e.g. durvalumab
  • Administration can be performed using cyclic administration as described herein.
  • Triple therapy is also contemplated herein (e.g., addition of a second compound or a second checkpoint inhibitor as described herein, addition of one or more secondary active agents as described herein or addition of another combination therapy as described herein).
  • Administration of the components of a combination therapy as described herein can occur simultaneously or sequentially as described above by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the cancer being treated.
  • the route of administration of a compound provided herein is independent of the route of administration of a checkpoint inhibitor as described herein.
  • lenalidomide and/or pomalidomide is administered orally (PO).
  • a compound provided herein is administered intravenously (IV).
  • a CPI described herein is administered intravenously.
  • a CPI described herein is administered in accordance with a package insert.
  • package insert refers to instructions customarily included in commercial packages of medicaments approved by the FDA or a similar regulatory agency of a country other than the USA, which contains information about, for example, the usage, dosage, administration, contraindications, and/or warnings concerning the use of such medicaments.
  • a secondary active agent described herein can be administered, for example, orally or intravenously.
  • a secondary active agent used in a combination described herein is administered in accordance with a package insert.
  • a combination described herein can include a compound provided herein (e.g., lenalidomide or pomalidomide) where the compound is administered orally, and the second therapy (e.g. a checkpoint inhibitor described herein) can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially,
  • a compound provided herein e.g., lenalidomide or pomalidomide
  • the second therapy e.g. a checkpoint inhibitor described herein
  • a compound provided herein e.g., lenalidomide or pomalidomide
  • a checkpoint inhibitor provided herein are administered by the same mode of administration, e.g., orally (PO) or by IV.
  • a compound provided herein e.g., lenalidomide or pomalidomide
  • one mode of administration e.g., orally
  • a checkpoint inhibitor provided herein is administered by another mode of administration, e.g., IV.
  • a combination described herein can include a CPI where the CPI is administered intravenously, and one or more secondary active agents described herein where the secondary active agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a checkpoint inhibitor provided herein and a secondary active agent described herein are administered by the same mode of administration, e.g., IV.
  • a checkpoint inhibitor provided herein is administered by one mode of administration, e.g., by IV, whereas a secondary active agent provided herein is administered by at least one different mode of administration, e.g., PO.
  • combination therapies described herein can also be combined or used in combination with other therapeutic agents (e.g., secondary active agents) useful in the treatment and/or prevention of cancer described herein. Such therapies can be referred to herein as “triple therapies.”
  • combination therapy as described herein with one or more secondary active agents (e.g., prophylactic and/or therapeutic agents) described herein.
  • Administration of a secondary active agent in combination with a combination therapy as described herein does not restrict the order in which any of therapies are administered to a patient with a disease or disorder.
  • a first therapy and a second therapy can be administered as set forth above and one or more secondary active agents can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
  • each component e.g., a compound described herein or checkpoint inhibitor described herein.
  • the suitability of a particular route of administration employed for a particular secondary active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream), the cancer being treated, and patient tolerance.
  • the secondary active agent is administered in accordance with a package insert.
  • the secondary active agent can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally,
  • a secondary active agent is administered orally or by IV.
  • the secondary active agent is formulated together with a combination therapy as described herein. Such formulations include those set forth herein and can be supplied as components of kits described herein.
  • Secondary active agents can include anti-cancer agents.
  • Exemplary secondary active agents include, but are not limited to: ace-11; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine;; docetaxel;
  • doxorubicin doxorubicin hydrochloride
  • enloplatin etoposide; etoposide phosphate; etoprine; floxuridine; fludarabine phosphate; fluorouracil; gemcitabine; gemcitabine hydrochloride;
  • herceptin hydroxyurea; ibrutinib; idarubicin hydrochloride; irinotecan; irinotecan hydrochloride; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; mycophenolic acid; rituximab; romidepsin; spiromustine; spiroplatin; stem cell treatments such as PDA-001;
  • streptonigrin streptozocin; sulofenur; teloxantrone hydrochloride; thiamiprine; thioguanine; uracil mustard; vincristine sulfate; zinostatin; and zorubicin hydrochloride.
  • Other examples include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; ALL-TK antagonists; angiogenesis inhibitors; antagonist D; antagonist G; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
  • docosanol docosanol; epirubicin; etoposide phosphategelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; idramantone; ilmofosine; ilomastat; imatinib immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone;
  • the secondary active agents include ibrutinib, bendamustine, or rituximab (a CD20 specific chimeric
  • the secondary active agent is oblimersen GM-CSF, G-CSF, SCF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.
  • the secondary active agent is a proteasome inhibitor.
  • the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor is bortezomib.
  • the proteasome inhibitor is carfilzomib.
  • the proteasome inhibitor is ixazomib.
  • the secondary active agent is an antibody.
  • the antibody is riuximab, tositumomab, ibritumomab tiuxetan, campath 1H, HULD10, Appratuzumab, LMB-2, BL22, HuM291, HeFi-1, VH4-34, CTLA4-lg,or anti- CTLA-4.
  • the secondary active agent is ibrutinib, bendamustine, rituximab, or a combination thereof.
  • the secondary active agent is ibrutinib.
  • the combination described herein includes a PD-L1 inhibitor (e.g. a PD-L1 antibody) and ibrutinib.
  • the combination described herein includes durvalumab and ibrutinib, where the combination (and each component thereof) are administered as described herein.
  • the combination includes administration of durvalumab via IV and ibrutinib via PO.
  • the secondary active agent is rituximab.
  • a combination described herein can include a PD-L1 inhibitor (e.g. a PD-L1 antibody), a compound described herein (e.g. lenalidomide or pomalidomide) and rituximab.
  • a PD-L1 inhibitor e.g. a PD-L1 antibody
  • a compound described herein e.g. lenalidomide or pomalidomide
  • rituximab e.g. lenalidomide or pomalidomide
  • the combination described herein includes durvalumab, lenalidomide, and rituximab, where the combination (and each component thereof) are administered as described herein.
  • the combination described herein includes durvalumab,
  • the secondary active agent is a combination of rituximab and bendamustine.
  • a combination described herein can include a PD-L1 inhibitor (e.g. a PD-L1 antibody) and rituximab/bendamustine.
  • the combination described herein includes durvalumab and rituximab/bendamustine, where the combination (and each component thereof) are administered as described herein.
  • the secondary active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
  • the specific amount of the secondary active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of any optional additional active agents concurrently administered to the patient.
  • the secondary active agent can be administered using cyclic therapy as described herein.
  • the secondary active agent is rituximab and can be administered at a concentration of 375 mg/m 2 .
  • the secondary active agent is rituximab and can be administered at a concentration of 500 mg/m 2 .
  • the secondary active agent is rituximab and is administered in accordance with a package insert.
  • rituximab is administered on days 1 and 8 of cycle 1 (e.g., the first cycle). In another embodiment, rituximab is administered on days 1, 8, 15, and 22 of cycle 1 (e.g., the first cycle). In such embodiments, rituximab can be administered at a concentration of 375 mg/ m 2 . In another embodiment, rituximab is administered at 375 mg/m 2 once weekly (e.g., days 2, 8, 15, and 22 of cycle 1) and on day one of each subsequent cycle (e.g., 2-5 cycles). Rituximab can further be administered on day one of every additional cycle in a 28-day cycle at a concentration of 500 mg/ m 2 .
  • rituximab can be administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles and optionally between 1-5 total cycles.
  • Secondary active agents described herein can be administered in accordance with established protocols known in the art (e.g., marketed compositions).
  • the secondary active agent is bendamustine and can be administered at a concentration of 100 mg/m 2 . In another embodiment the secondary active agent is bendamustine and can be administered at a concentration of 120 mg/m 2 . In still another embodiment the secondary active agent is bendamustine and is administered in accordance with a package insert. In one embodiment, bendamustine is administered on days 1 and 2 of cycle 1 (e.g., the first cycle). Bendamustine can further be administered on day one and two of every additional cycle in a 28-day cycle. In such embodiments, bendamustine can be administered over 1, 2, 3, 4, 5, or 6 cycles. In certain instances, the amount of bendamustine administered in a combination described herein is lowered due to toxicity development in the subject. In such occurrences, the amount of bendamustine administered can be reduced to about 50, 60, 70, 80, or 90 mg/m 2 .
  • the combination includes two secondary active agents selected from rituximab and bendamustine where each agent is administered as described above.
  • the secondary active agent is ibrutinib and can be administered at an amount of about 420 mg. In still another embodiment the secondary active agent is ibrutinib and can be administered at an amount of about 560 mg. In still another embodiment the secondary active agent is ibrutinib and is administered in accordance with a package insert. In embodiments, ibrutinib is administered orally once daily.
  • the secondary active agent when the secondary active agent is GM-CSF, G-CSF, SCF or EPO, such secondary active agents are administered subcutaneously during about five days in a four or six week cycle in an amount ranging from about 1 to about 750 mg/m 2 /day, from about 25 to about 500 mg/m 2 /day, from about 50 to about 250 mg/m 2 /day, or from about 50 to about 200 mg/m 2 /day.
  • the secondary active agent when the secondary active agent is GM-CSF, it may be administered in an amount of from about 60 to about 500 mcg/m 2 intravenously over 2 hours or from about 5 to about 12 mcg/m 2 /day subcutaneously.
  • the secondary active agent when the secondary active agent is G-CSF, it may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts.
  • the maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 meg subcutaneously.
  • the secondary active agent when the secondary active agent is EPO, it may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
  • a therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, or from about 1 to about 100 mg per day.
  • lenalidomide or pomalidomide is administered in an amount from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day.
  • a therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, or from about 0.01 to about 250 mg per day.
  • lenalidomide or pomalidomide is administered in the combinations described herein in an amount from about 1 to about 25 mg per day, from about 2.5 to about 25 mg per day, from about 5 to about 25 mg per day, from about 10 to about 25 mg per day, from about 0.05 to about 10 mg per day, 0.5 to about 10 mg per day, 0.5 to about 5 mg per day, 1 to about 10 mg per day, or about 1 to 5 mg per day.
  • the therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is about 0.1, about 0.2, about 0.3. about 0.5, about 1, about 2, about 2.5, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.
  • lenalidomide is administered in an amount of about 1, 2.5, 5, 10, 15, 20, 25, or 50 mg per day.
  • lenalidomide is
  • pomalidomide is administered in an amount of about 0.5, 1, 2, 3, 4 or 5 mg per day.
  • the recommended daily dose range of a compound described herein for use in a combination therapy as described herein lie within the range of from about 0.5 mg to about 50 mg per day, preferably given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.01, 0.05,.
  • the recommended starting dosage of a compound described herein for use in a combination therapy as described herein may be 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day.
  • the compound described herein is lenalidomide and has a recommended starting dosage of 1, 2.5, 5, 10, 15, 20, 25, or 50 mg.
  • the compound is lenalidomide at a starting dosage of 2.5, 5, 10, 25, or 50 mg.
  • the compound is lenalidomide at a starting dosage of 2.5, 5, 10, or 25 mg.
  • the recommended starting dosage of a compound described herein for use in a combination therapy as described herein may be 0.5, 1, 2, 3, 4, or 5 mg per day.
  • the compound described herein is pomalidomide and has a
  • a compound described herein for use in a combination therapy as described herein can be administered in an amount of about 25 mg/day to patients with NHL (e.g., DLBCL). In a particular embodiment, of a compound described herein for use in a combination therapy as described herein can be administered in an amount of about 10 mg/day to patients with NHL (e.g., DLBCL).
  • the therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 to about 1 mg/kg/day.
  • the administered dose can also be expressed in units other than mg/kg/day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm).
  • a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m 2 /day.
  • a plasma concentration of the compound at steady state ranging from about 0.001 to about 500 ⁇ , about 0.002 to about 200 ⁇ , about 0.005 to about 100 ⁇ , about 0.01 to about 50 ⁇ , from about 1 to about 50 ⁇ , about 0.02 to about 25 ⁇ , from about 0.05 to about 20 ⁇ , from about 0.1 to about 20 ⁇ , from about 0.5 to about 20 ⁇ , or from about 1 to about 20 ⁇ .
  • the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.
  • plasma concentration at steady state is the concentration reached after a period of administration of a compound provided herein, e.g., a compound provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.
  • the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 500 ⁇ , about 0.002 to about 200 ⁇ , about 0.005 to about 100 ⁇ , about 0.01 to about 50 ⁇ , from about 1 to about 50 ⁇ , about 0.02 to about 25 ⁇ , from about 0.05 to about 20 ⁇ , from about 0.1 to about 20 ⁇ , from about 0.5 to about 20 ⁇ , or from about 1 to about 20 ⁇ .
  • the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 ⁇ , about 0.002 to about 200 ⁇ , about 0.005 to about 100 ⁇ , about 0.01 to about 50 ⁇ , from about 1 to about 50 ⁇ , about 0.01 to about 25 ⁇ , from about 0.01 to about 20 ⁇ , from about 0.02 to about 20 ⁇ , from about 0.02 to about 20 ⁇ , or from about 0.01 to about 20 ⁇ .
  • the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL.
  • AUC area under the curve
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a
  • combination therapy as described herein at an amount of about 1 mg to about 25 mg per day.
  • lenalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a combination therapy as described herein at an amount of about 1 mg to about 25 mg per day.
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a combination therapy as described herein at an amount of about 0.5 mg to about 5 mg per day.
  • pomalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a combination therapy as described herein at an amount of about 0.5 mg to about 5 mg per day.
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a combination therapy as described herein at an amount of about 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per day.
  • Checkpoint inhibitors described herein for use in a combination therapy described herein can be administered in amounts from about 0.005 to about 2,000 mg per day, from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day.
  • a checkpoint inhibitor described herein is administered in an amount from about 500 mg to about 2500 mg, 750 mg to about 2250 mg, 1000 mg to about 2000 mg, or about 1200 mg to about 1800 mg.
  • Checkpoint inhibitors described herein can be administered in a therapeutically effective amount of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or about 2500 mg.
  • the checkpoint inhibitor is administered in a therapeutically effective amount of about 1000, 1250, 1500, 1750, or 2000 mg.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is durvalumab.
  • Durvalumab can be administered in an amount from 1 mg to about 2,000 mg per day, from about 100 mg to about 2,000 mg per day, from about 250 mg to about 2,000 mg per day, from about 500 mg to about 2,000 mg per day, 1 mg to about 1,500 mg per day, from about 100 mg to about 1,500 mg per day, from about 250 mg to about 1,500 mg per day, from about 500 mg to about 1,500 mg per day, 1 mg to about 1,000 mg per day, from about 100 mg to about 1,000 mg per day, from about 250 mg to about 1,000 mg per day, from about 500 mg to about 1,000 mg per day, from about 250 mg to about 750 mg per day, or from about 400 mg to about 600 mg per day.
  • the checkpoint inhibitor is durvalumab administered at an amount of about 100, 250, 500, 1,000, 1,500, or 2,000 mg per day.
  • the CPI is durvalumab it can be administered at a concentration of about 1500 mg.
  • the CPI is durvalumab it can be administered at a concentration of about 50 mg/mL.
  • a combination therapy as described herein is co-administered to a patient receiving radiation therapy (e.g., local involved field radiation therapy (IFRT)).
  • IFRT local involved field radiation therapy
  • the patient to be treated with a combination therapy described herein has not been treated with anticancer therapy prior to the administration the combination therapy.
  • the patient to be treated with a combination therapy described herein has been treated with anticancer therapy prior to administration of a compound described herein for use in a combination therapy described herein.
  • the patient to be treated with a combination therapy described herein has developed drug resistance to, or has a cancer that is refractory to, at least one anticancer therapy.
  • Checkpoint inhibitors provided herein can be administered according to the routes and dosage amounts generally known to a person of ordinary skill in the art.
  • a checkpoint inhibitor described herein is administered in accordance with established protocols known in the art (e.g., marketed compositions).
  • Secondary active agents described herein e.g. rituximab, ibrutinib, bendamustine
  • a secondary active agent described herein is administered according to the routes and dosage amounts generally known to a person of ordinary skill in the art.
  • a secondary active agent described herein is administered in accordance with established protocols known in the art (e.g., marketed compositions).
  • Dosages of compounds described herein, checkpoint inhibitors described herein, and secondary active agents described herein can be modified (e.g., increased or decreased dosage) during treatment as set forth herein and understood in the art.
  • the combination therapies described herein including components therein (e.g., a compound as described herein and a CPI as described herein or a CPI and one or more secondary active agents) are cyclically administered to a patient.
  • the combination therapies described herein are administered cyclically as described herein and a secondary active agent is co-administered in a cyclic administration with such combination therapies.
  • Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can be performed independently for each active agent (e.g., a compound described herein, a CPI described herein, and/or a secondary agent described herein) over a prescribed duration of time.
  • each active agent is dependent upon one or more of the active agents administered to the subject.
  • administration of a compound or checkpoint inhibitor described herein fixes the day(s) or duration of administration of each agent.
  • administration of a compound or checkpoint inhibitor described herein fixes the days(s) or duration of administration of a secondary active agent.
  • a compound described herein, a CPI described herein, and/or a secondary active agent described herein is administered continually (e.g., daily, weekly, monthly) without a rest period. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment or therapeutic agent.
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered as a component of a combination therapy as described herein once daily for 28 consecutive days in a 28 days cycle.
  • combination therapies include administration of a CPI as described herein on one or more days of
  • a compound as described herein is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle.
  • a combination therapy includes administration of a CPI as described herein on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the compounds described herein and CPIs described herein of such a combination can be present at a
  • the combination therapy includes administration of a compound described herein consecutively for 21 days of a 28 days cycle and administration of a CPI on at least one day of each cycle (e.g., day 1 of cycle 1) in combination with a secondary active agent administered on at least one day of each cycle.
  • a secondary active agent can be administered once daily, once weekly, or once monthly during the cycling therapy.
  • the secondary active agent is administered once weekly in combination with a combination therapy described herein.
  • the combination therapy includes lenalidomide as described herein and durvalumab as described herein, where lenalidomide is administered once daily for 21 consecutive days followed by 7 days rest in a 28 days cycle and durvalumab is administered on day one of each 28 days cycle.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (i.e., 12 months).
  • Lenalidomide can be administered at a concentration or amount as described herein.
  • lenalidomide is administered at an amount of about 5 mg to about 25 mg.
  • Durvalumab can be administered at a concentration described herein.
  • durvalumab is administered at an amount of about 1,000 mg to about 2,000 mg.
  • the combination therapy includes a secondary active agent as described herein.
  • the secondary active agent is rituximab administered in an amount described herein.
  • the secondary active agent is ibrutinib administered in an amount described herein.
  • the secondary active agent is bendamustine administered in an amount described herein.
  • the secondary agent includes a combination of rituximab and bendamustine each of which are administered in an amount as described herein.
  • Secondary active agents can be administered once or over a predetermined period of time such as, for example, daily, weekly, or monthly. In one embodiment the secondary active agent is administered once daily.
  • the secondary active agent is administered on the first two days of the first cycle and optionally on the first two days of each additional cycle. In one embodiment the secondary active agent is administered once weekly. In one embodiment the secondary active agent is administered once monthly. In another embodiment the secondary active agent is administered about every 7 days for the first cycle and on day 1 of each subsequent cycle. In one embodiment the secondary active agent is rituximab. When the secondary active agent is rituximab, it can be administered intravenously. In one embodiment, the combination is administered according to Table 17.
  • the combination therapy includes pomalidomide as described herein and durvalumab as described herein, where pomalidomide is administered once daily for 21 consecutive days followed by 7 days rest in a 28 days cycle and durvalumab is administered on day one of each 28 days cycle.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (i.e., 12 months).
  • Pomalidomide can be administered at a concentration or amount as described herein.
  • pomalidomide is administered at an amount of about 5 mg to about 25 mg.
  • Durvalumab can be administered at a concentration described herein.
  • durvalumab is administered at an amount of about 1,000 mg to about 2,000 mg.
  • the combination therapy includes a secondary active agent as described herein.
  • the secondary active agent is rituximab administered in an amount described herein.
  • the secondary active agent is ibrutinib administered in an amount described herein.
  • the secondary active agent is bendamustine administered in an amount described herein.
  • the secondary agent includes a combination of rituximab and bendamustine each of which are administered in an amount as described herein.
  • Secondary active agents can be administered once or over a predetermined period of time such as, for example, daily, weekly, or monthly. In one embodiment the secondary active agent is administered once daily.
  • the secondary active agent is administered on the first two days of the first cycle and optionally on the first two days of each additional cycle. In one embodiment the secondary active agent is administered once weekly. In one embodiment the secondary active agent is administered once monthly. In another embodiment the secondary active agent is administered about every 7 days for the first cycle and on day 1 of each subsequent cycle. In one embodiment the secondary active agent is rituximab. When the secondary active agent is rituximab, it can be administered intravenously.
  • lenalidomide or pomalidomide can independently be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID) as part of a combination therapy described herein.
  • the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • the term “daily” is intended to mean that a therapeutic agent is administered once or more than once each day, for example, for a period of time.
  • continuous is intended to mean that a therapeutic agent is administered daily for an uninterrupted period of at least 10 days to 52 weeks.
  • intermittent or
  • intermittently as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound for use in
  • combination therapies described herein can be administered for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • cycling as used herein is intended to mean that a therapeutic agent is administered daily or continuously but with a rest period.
  • the frequency of administration is in the range of about a daily dose to about a monthly dose.
  • administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks.
  • a compound for use in combination therapies described herein e.g. lenalidomide or
  • pomalidomide is administered once a day.
  • a compound for use in combination therapies described herein e.g. lenalidomide or pomalidomide
  • a compound for use in combination therapies described herein is administered twice a day.
  • a compound for use in combination therapies described herein is administered three times a day.
  • a compound for use in combination therapies described herein is administered four times a day.
  • a compound for use in combination therapies described herein is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks.
  • a compound for use in combination therapies described herein is administered once per day for one week, two weeks, three weeks, or four weeks.
  • a compound for use in combination therapies described herein is administered once per day for one week, two weeks, three weeks, or four weeks.
  • a compound for use in combination therapies described herein e.g. lenalidomide or pomalidomide
  • pomalidomide is administered once per day for one week.
  • a compound for use in combination therapies described herein is administered once per day for two weeks.
  • a compound for use in combination therapies described herein e.g. lenalidomide or pomalidomide
  • a compound for use in combination therapies described herein e.g. lenalidomide or pomalidomide
  • a checkpoint inhibitor for use in combination therapies described herein can independently be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID) as part of a combination therapy described herein.
  • the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • intermittent administration of a checkpoint inhibitor for use in combination therapies described herein can be administered for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • intermittent administration of a checkpoint inhibitor for use in combination therapies described herein can be administered for once per month, administration in cycles (e.g., monthly administration for two to twelve cycles).
  • the frequency of administration is in the range of about a daily dose to about a monthly dose.
  • administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks.
  • a checkpoint inhibitor for use in combination therapies described herein is administered once a month (e.g. day 1 of each cycle).
  • a checkpoint inhibitor for use in combination therapies described herein is administered twice a month.
  • a checkpoint inhibitor for use in combination therapies described herein is administered three times a month.
  • a checkpoint inhibitor for use in combination therapies described herein is administered four times a month (e.g., weekly).
  • compositions and dosage forms which include a combination therapy as described herein.
  • pharmaceutical compositions and dosage forms that include a combination therapy as described herein and one or more secondary active agents as set forth herein.
  • Such pharmaceutical compositions and dosage forms can include one or more excipients.
  • compositions including the individual components of the
  • Single unit dosage forms can be supplied as single unit dosage forms.
  • Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or
  • compositions described herein include components supplied as different formulations (e.g. a compound described herein supplied as a oral dosage, a CPI described herein supplied as an IV dosage, and a secondary active agent described herein supplied as an oral dosage or an IV dosage).
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories;
  • liquid dosage forms suitable for oral or mucosal administration to a patient including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions
  • solutions elixirs
  • liquid dosage forms suitable for parenteral administration to a patient eye drops or other ophthalmic preparations suitable for topical administration
  • sterile solids e.g., crystalline
  • composition, shape, and type of dosage forms provided herein may vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form provided herein depends on a variety of factors, including, but not limited to, the route of administration.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, encompassed herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions can comprise excipients that are listed, for example, in the U.S. Pharmacopeia (USP) 25 F20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, in certain embodiments, provided herein are anhydrous compositions packaged using materials to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
  • the dosage forms provided herein include one or more compounds described herein in an amount described herein (e.g., ranging from about 0.10 to about 1000 mg, from about 0.10 to about 500 mg, from about 0.10 to about 200 mg, from about 0.10 to about 150 mg, from about 0.10 to about 100 mg, from about 0.10 to about 50 mg, from about 0.5 to about 10 mg, from about 1 to about 10 mg, from about 1 to about 20 mg, or from about 1 to about 25 mg).
  • an amount described herein e.g., ranging from about 0.10 to about 1000 mg, from about 0.10 to about 500 mg, from about 0.10 to about 200 mg, from about 0.10 to about 150 mg, from about 0.10 to about 100 mg, from about 0.10 to about 50 mg, from about 0.5 to about 10 mg, from about 1 to about 10 mg, from about 1 to about 20 mg, or from about 1 to about 25 mg).
  • the dosage forms provided herein include one or more compounds described herein in an amount of about 0.1, about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, about 50, about 100, about 150, or about 200 mg.
  • the dosage forms provided herein include a checkpoint inhibitor described herein in an amount described herein (e.g., ranging from about 1 to about 2000 mg, from about 10 to about 2000 mg, from about 1 to about 1500 mg, from about 10 to about 1500 mg, 1 to about 1000 mg, from about 10 to about 1000 mg, from about 500 to about 2000 mg, from about 500 to about 1500 mg, from about 500 to about 1000 mg, from about 1000 to about 2000 mg, or from about 1000 to about 1500 mg.
  • a checkpoint inhibitor described herein in an amount described herein (e.g., ranging from about 1 to about 2000 mg, from about 10 to about 2000 mg, from about 1 to about 1500 mg, from about 10 to about 1500 mg, 1 to about 1000 mg, from about 10 to about 1000 mg, from about 500 to about 2000 mg, from about 500 to about 1500 mg, from about 500 to about 1000 mg, from about 1000 to about 2000 mg, or from about 1000 to about 1500 mg.
  • the dosage forms provided herein include one or more checkpoint inhibitors described herein in an amount of about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or about 2000 mg.
  • compositions provided herein that are suitable for oral administration are formulated as discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients and may be prepared by some known methods of pharmacy. See generally, Remington's
  • the oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by some known methods of pharmacy. In certain embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. [00275] In certain embodiments, a tablet is prepared by compression or molding.
  • compressed tablets are be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient.
  • molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL- PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL RC- 581).
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • agar-agar alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • compositions and dosage forms described herein do not contain croscarmellose sodium.
  • Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, MD), a coagulated aerosol of synthetic silica (Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, MA), and mixtures thereof.
  • a syloid silica gel AEROSIL200, W.R. Grace Co., Baltimore, MD
  • a coagulated aerosol of synthetic silica Degussa Co. of Piano, TX
  • CAB-O-SIL a pyrogenic silicon dioxide, Cabot Co. of Boston, MA
  • lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • pharmaceutical compositions and dosage forms described herein do not include magnesium stearate.
  • the active ingredients provided herein are administered by controlled-release or slow means, or by delivery devices.
  • Examples include, but are not limited to, those described in U.S. Patent Nos. : 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5, 120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety.
  • such dosage forms are used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • single unit dosage forms suitable for oral administration including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release or slow release.
  • controlled-release or slow release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- release or slow release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • drug active ingredient
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as,
  • Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms provided herein.
  • cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5, 134,127, the disclosure of which is incorporated herein by reference in its entirety.
  • Topical and mucosal dosage forms include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • excipients e.g., carriers and diluents
  • other materials that can be used to provide topical and mucosal dosage forms encompassed herein depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • the excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are nontoxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Additional examples of such ingredients can be found, e.g., in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).
  • the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • hematological cancer or solid tumors are methods of treating, preventing, and/or managing hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein.
  • a method of managing hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein.
  • Such combinational therapies include all therapies as provided above (e.g., combination therapies including a compound described herein (e.g. lenalidomide or pomalidomide) together with a CPI described herein and optionally one or more secondary active agents described herein and combination therapies including a CPI described herein together with one or more secondary active agents described herein).
  • Patients benefitting from the methods described herein can include patients who have been previously treated for cancer but are non-responsive to standard therapies. In such instances patients may be non-responsive or have developed resistance to anti-cancer treatments. Patients may have cancer refractory or otherwise non-response to at least one anticancer therapy. Patients may also include patients who have not previously been treated by administering a component of a combination therapy as described herein. Patients can also include those patients who have undergone surgery in an attempt to treat the disease or condition at issue. The methods and combination therapies described herein are equally applicable to patients who have not undergone surgery prior to administration. Patients currently taking agents for treating cancer (e.g., concurrently chemotherapy, immunotherapy, biologies, or hormonal therapy), in certain instances, may be excluded from the methods described herein.
  • agents for treating cancer e.g., concurrently chemotherapy, immunotherapy, biologies, or hormonal therapy
  • Treatment may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including expression levels of checkpoint proteins as identified herein), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others.
  • OS as used herein means the time from treatment onset until death from any cause.
  • TTP as used herein means the time from treatment onset until tumor progression; TTP does not comprise deaths.
  • PFS means the time from treatment onset until tumor progression or death. In the extreme, complete inhibition, is referred to herein as prevention or chemopreventi on .
  • the treatment can be assessed by one or more clinical endpoints selected from positive tumor response, complete response, partial response or stable disease, increased survival without tumor progression, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor- related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), or increased Overall Survival (OS).
  • TTP Time To Progression
  • PFS Progression Free Survival
  • OS Overall Survival
  • a patient described herein can show a positive tumor response, such as inhibition of tumor growth or a reduction in tumor size after treatment with a combination described herein.
  • a patient described herein can achieve a Response Evaluation Criteria in Solid Tumors (for example, RECIST 1.1) of complete response, partial response or stable disease after administration of an effective amount a combination described.
  • a patient described herein can show increased survival without tumor progression.
  • a patient described herein can show inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including tumor secreted hormones, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and/or increased Overall Survival (OS), among others.
  • TTP Time To Progression
  • PFS Progression Free Survival
  • OS Overall Survival
  • methods are provided for increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein.
  • a method is provided for increasing the overall survival of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein.
  • the combination can be administered so that it includes lenalidomide or pomalidomide in combination with a CPI as described herein.
  • the methods described herein are methods useful for treating, preventing, and/or managing cancer of the skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus.
  • cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B
  • the hematological cancer is myeloma, lymphoma or leukemia.
  • the hematological cancer is myeloma, lymphoma or leukemia.
  • the cancer is myeloma.
  • the cancer is lymphoma.
  • the hematological cancer is lymphoma or chronic lymphocytic leukemia (CLL).
  • the hematological cancer is Hodgkin lymphoma (HL) or CLL. In one embodiment the hematological cancer is CLL. In one embodiment the hematological cancer is HL. In one embodiment the hematological cancer is non-Hodgkin's lymphoma (NHL). In certain embodiments the hematological cancer includes indolent lymphomas including for example DLBCL, follicular lymphoma, or marginal zone lymphoma. In another embodiment the hematological cancer is a cancer set forth in Table 1. In certain embodiments, the hematological cancer is drug resistant to at least one anticancer therapy. In certain embodiments the hematological cancer is refractory to at least one anticancer therapy.
  • the hematological cancer is metastatic.
  • methods for increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having myeloma, leukemia, or lymphoma as described herein comprising administering an effective amount of a combination as described herein.
  • the B-cell malignancy is selected from the group consisting of mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B- cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), and modular lymphocyte pre-dominant Hodgkin lymphoma.
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • Burkitt lymphoma Burkitt lymphoma
  • MZL marginal-zone lymphoma
  • splenic variants including splenic variants, diffuse large B- cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL),
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • Burkitt lymphoma marginal-zone lymphoma (MZL) including splenic variants, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), or modular lymphocyte pre-dominant Hodgkin lymphoma comprising administering an effective amount of a combination as described herein.
  • DLBCL diffuse large B-cell lymphoma
  • LPL lymphoplasmacytic lymphoma
  • MM multiple myeloma
  • HL classical type Hodgkin lymphoma
  • HL modular lymphocyte pre-dominant Hodgkin lymphoma
  • Table 1 Exemplary B-cell Non-Hodgkin Lymphoma Histologies (Based on the 2008 WHO Lymphoma Classification) for Phase 1 Dose Finding Cohorts
  • ALK Anaplastic Lymphoma Kinase
  • WHO World Health Organization ⁇ Transformed lymphoma will be included (but is not part of the WHO 2008 Classification).
  • a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no
  • the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary active agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the secondary active agent is rituximab.
  • a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the combination for treating a B-cell malignancy described herein includes lenalidomide, a PD-L1 inhibitor, and a proteasome inhibitor.
  • the combination can further include dexamethasone.
  • the combination includes lenalidomide, dexamethasone, and durvalumab.
  • the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
  • the method is a method of treating or managing non-Hodgkin's lymphoma by administering a combination therapy described herein to a subject in need thereof.
  • DLBCL diffuse large B-cell lymphoma
  • R/R relapsed/refractory lymphoma
  • FL follicular lymphoma
  • the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary active agent is administered weekly.
  • the combination therapy is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary active agent is administered weekly.
  • the combination therapy is
  • the secondary active agent is rituximab.
  • a method of treating NHL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • a method of treating NHL by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • a method of treating NHL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein.
  • a method of treating NHL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having NHL.
  • a method of treating diffuse large B-cell lymphoma by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • pomalidomide administered at an amount and frequency as described herein e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having DLBCL.
  • the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating FL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
  • the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • a method of treating FL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein.
  • a method of treating FL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having FL.
  • a method of treating marginal zone lymphoma by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating MZL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having MZL.
  • a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the multiple myeloma is relapsed multiple myeloma. In one embodiment, the multiple myeloma is refractory multiple myeloma. In one embodiment, the multiple myeloma is relapsed/refractory (R/R) multiple myeloma. In one embodiment, the patient having R/R multiple myeloma has impaired renal function. In one embodiment, the multiple myeloma is newly diagnosed multiple myeloma. In one embodiment, the multiple myeloma is smoldering multiple myeloma.
  • a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • a method of treating multiple myeloma by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or
  • the second active agent is lenalidomide. In another embodiment, the second active agent is pomalidomide.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having multiple myeloma.
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • CLL chronic lymphocytic leukemia
  • the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating CLL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the second active agent is lenalidomide. In another embodiment, the second active agent is pomalidomide.
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having CLL.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having CLL.
  • the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
  • the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle)
  • durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein.
  • a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
  • the carcinoma is a carcinoma as described herein and in certain embodiments is primary ductal carcinoma, lung carcinoma, colon adenocarcinoma, histiocytic lymphoma, colorectal carcinoma, hepatocellular carcinoma, or colorectal adenocarcinoma.
  • the method is a method of treating, preventing, and/or managing a sarcoma described herein.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having carcinoma or sarcoma.
  • MDS myelodysplastic syndromes
  • the MDS can be a low risk MDS (LR MDS).
  • the MDS can be a high risk MDS (HR MDS).
  • the MDS develops into acute myelogenous leukemia (AML).
  • the MDS develops into chronic myelogenous leukemia (CML).
  • the MDS develops into acute lymphocytic leukemia (ALL).
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • the MDS is resistant to treatment with hypomethylating agents (HMAs).
  • the MDS is developed from a treatment with a therapy (tMDS), e.g., therapy induced.
  • the combination therapy includes a CPI described herein and one or more secondary active agents.
  • the CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
  • a method of treating myelodysplastic syndromes by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein.
  • a method of treating myelodysplastic syndromes by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
  • the combination for treating MDS includes lenalidomide, a PD- Ll inhibitor, and a proteasome inhibitor.
  • the combination can further include dexamethasone.
  • the combination includes lenalidomide, dexamethasone, and durvalumab.
  • the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having MDS.
  • AML can be R/R AML, trilineage dysplasia AML (AML-TLD), or therapy induced AML (tAML).
  • AML-TLD trilineage dysplasia AML
  • tAML therapy induced AML
  • the patient is as described herein and in certain instances has undergone treatment with a HMA.
  • the patient has HMA refractory AML.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having AML.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having ALL.
  • a method of treating CML in a subject in need thereof by administering a combination therapy as described herein can be R/R CML.
  • a combination therapy described herein is co-administered according to the methods and description herein with a secondary active agent.
  • the secondary active agent can be an anticancer agent as described herein.
  • the secondary active agent is a tyrosine kinase inhibitor (TKI).
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having CML.
  • administering modulates expression levels of at least one CPI described herein (e.g., PD-L1).
  • CPI described herein
  • methods of determining the expression of at least one CPI where the determination of the expression level is performed before, during, and/or after administration of a combination therapy described herein.
  • the CPI expression levels determined before, during, and/or after administration of a combination therapy as described herein can be compared against each other or standard controls. Such comparisons can translate into determination of the efficacy of the administered treatment where in one embodiment a level of decreased expression of a given CPI indicates a greater effectiveness of the combination therapy.
  • the combination therapies described herein reduce or eliminate minimal residual disease (MRD) state of a MDS described herein. Accordingly, in one embodiment a combination therapy described herein is administered to a patient in need thereof, wherein said administration reduces or eliminates MRD. In one embodiment, the combination therapy is administered after administration of chemotherapy. In another embodiment, the combination therapy is administered during chemotherapy. In yet another embodiment, the combination therapy is administered as a chemotherapeutic therapy.
  • MRD minimal residual disease
  • a combination therapy described herein is administered before or after a stem cell transplant (SCT) such as a bone marrow stem cell transplant (BMSCT).
  • SCT stem cell transplant
  • BMSCT bone marrow stem cell transplant
  • the level of expression of a CPI is determined for such stem cells pre- and post- transplant and pre- and post- administration with a combination therapy as described herein.
  • a combination therapy described herein is administered after a SCT (e.g., 1-24 hours, 1-3 days, 1-10 days, 1-3 months, 3-6 months, or 6-12 months post transplant).
  • a combination therapy described herein is administered within 180 days of a SCT.
  • administration of a combination therapy described herein reduces or eliminates development of graft v.
  • the stem cell transplant is a hematopoietic stem cell transplant.
  • the transplant is a peripheral blood transplant.
  • the stem cell transplant is an autologous stem cell transplant.
  • DLI donor lymphocyte infusion
  • VDL donor- versus-leukemia
  • DLI uses the collection (from the original donor) of peripheral lymphocytes during an apheresis procedure; donors generally undergo 2 to 8 procedures. The lymphocytes are then infused into the patient either immediately or after frozen storage.
  • Donor lymphocyte infusion differs from allogeneic bone marrow transplantation in that it is not preceded by chemotherapy and T cells are not depleted.
  • Lymphocyte infusion with a defined T-cell dose can cause a profound GVL effect and can be an effective form of salvage immunotherapy in allogeneic marrow transplanted recipients.
  • DLI lowers treatment-related morbidity and mortality when compared to second allogeneic transplantation.
  • CR complete remission
  • CR can be prolonged by administering the combination therapies described herein (and optionally with co-administration of secondary active agents described herein) for MDS including when MDS develops into AML, ALL, CML, and CLL as described herein.
  • administration of a combination therapy described herein prolongs complete remission (CR) of the cancer (e.g. solid tumor or
  • treatment using the combination therapies described herein can be monitored or determined using assays to determine expression levels of checkpoint proteins described herein (e.g., PD-L1, ⁇ -3, LAG-3, CTLA-4, OX40, Treg, CD25, CD127, FoxP3). Determining the expression of such checkpoint proteins can be performed before, during, or after completion of treatment with a combination therapy described herein. Expression can be determined using techniques known in the art, including for example flow-cytometry.
  • checkpoint proteins described herein e.g., PD-L1, ⁇ -3, LAG-3, CTLA-4, OX40, Treg, CD25, CD127, FoxP3
  • the MDS is drug resistant to at least one anticancer therapy. In certain embodiments the MDS is refractory to at least one anticancer therapy.
  • the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the combination therapy is
  • the MDS can develop into AML, CML, ALL, or CLL as described herein.
  • the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly.
  • the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
  • the MDS can develop into AML, CML, ALL, or CLL as described herein.
  • a method of treating MDS by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the MDS can develop
  • combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • lenalidomide administered at an amount and frequency as described herein e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle
  • durvalumab administered at an amount and frequency as described herein e.g., monthly in a 28 day cycle
  • one or more days of administration of the compound e.g., on day 1 of cycle 1
  • a method of treating MDS by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
  • the MDS can develop into AML, CML, ALL, or CLL as described herein.
  • combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
  • the MDS can develop into AML, CML, ALL, or CLL as described herein.
  • a combination therapy as described herein is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acute myelogenous leukemia.
  • a combination therapy as described herein is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
  • the solid tumor is metastatic.
  • the solid tumor is drug-resistant to at least one anticancer therapy.
  • the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma.
  • provided herein are methods of preventing relapsed/refractory multiple myeloma in patients by administering an effective amount of a combination therapy as described herein.
  • the patient may also have impaired renal function or a symptom thereof.
  • provided herein are methods for treating, preventing, and/or managing relapsed/refractory multiple myeloma in patients with impaired renal function by administering a combination therapy as described herein.
  • HCC hepatocellular carcinoma
  • a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
  • a combination therapy as described herein can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with
  • a method of treating, preventing and/or managing cancer which comprises administering a combination therapy described herein in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
  • conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
  • the combined use of the combination therapy described herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that the combination therapies described herein may provide additive or synergistic effects when given concurrently with conventional therapy.
  • a combination therapy as described herein for use in a method of treating, preventing and/or managing cancer wherein the method comprises the above defined administration step.
  • the cancer is glioblastoma, primary ductal carcinoma, leukemia, acute T cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid lymphoma (CML), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), lung carcinoma, colon adenocarcinoma, histiocytic lymphoma, colorectal carcinoma, colorectal adenocarcinoma, prostate cancer, non-Hodgkin lymphoma (e.g., DLBCL, MZL, or FL), multiple myeloma, or retinoblastoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid lymphoma
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • lung carcinoma colon adenocarcinoma
  • histiocytic lymphoma histiocy
  • the T-cell malignancy is selected from the group consisting of peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, angioimunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, lymphoblastic lymphoma, treatment related T-cell lymphoma; T-cell NHL, and chronic T-cell lymphoma.
  • the method includes a combination described herein where the combination includes an immunomodulatory compound selected from lenalidomide or pomalidomide.
  • the T-cell malignancy is peripheral T-cell lymphoma (not otherwise specified).
  • the T-cell malignancy is analplastic large cell lymphoma.
  • the T-cell malignancy is Sezary syndrome, primary cutaneous anaplastic large cell lymphoma or lymphomatoid papulosis.
  • the T-cell malignancy is angioimunoblastic lymphoma.
  • the T-cell malignancy is cutaneous T-cell lymphoma.
  • the T-cell malignancy is adult T-cell leukemia/lymphoma (ATLL).
  • the T-cell malignancy is blastic K-cell lymphoma.
  • the T-cell malignancy is lymphoblastic lymphoma. In one embodiment, the T-cell malignancy is treatment related T-cell lymphoma. In one embodiment, the T-cell malignancy is T-cell NHL. In one embodiment, the T-cell malignancy is chronic T- cell lymphoma.
  • the combination for treating a T-cell malignancy described herein includes lenalidomide, a PD-Ll inhibitor, and a proteasome inhibitor.
  • the combination can further include dexamethasone.
  • the combination includes lenalidomide, dexamethasone, and durvalumab.
  • the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
  • the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and
  • lymphomatoid papulosis angioimunoblastic lymphoma
  • cutaneous T-cell lymphoma cutaneous T-cell lymphoma
  • adult T- cell leukemia/lymphoma ATLL
  • blastic NK-cell lymphoma lymphoblastic lymphoma
  • treatment related T-cell lymphoma T-cell NHL, or chronic T-cell lymphoma.
  • a combination therapy as described herein is administered with melphalan and dexamethasone to patients with amyloidosis.
  • a combination therapy described herein and steroids can be administered to patients with amyloidosis.
  • a combination therapy as described herein is administered with rituximab for treating non-Hodgkin lymphoma (NHL).
  • NHS non-Hodgkin lymphoma
  • a combination therapy as described herein is administered with ibrutinib for treating non-Hodgkin lymphoma (NHL).
  • NHS non-Hodgkin lymphoma
  • a combination therapy as described herein is administered with bendamustine for treating non-Hodgkin lymphoma (NHL).
  • a combination therapy as described herein is administered with rituximab/bendamustine for treating non-Hodgkin lymphoma (NHL).
  • a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
  • lymphoma in another aspect is a method for treating lymphoma as described herein comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • Burkitt lymphoma marginal-zone lymphoma (MZL) including splenic variants, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), or modular lymphocyte pre-dominant Hodgkin lymphoma
  • a combination therapy as described herein is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
  • a combination therapy as described herein is administered in combination with a secondary active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapsed brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade
  • a combination therapy as described herein is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, or PLX3397
  • a combination therapy as described herein is administered with temozolomide to patients with neuroendocrine tumors.
  • a combination therapy as described herein is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.
  • a combination therapy as described herein is administered with gemcitabine to patients with pancreatic cancer.
  • a combination therapy as described herein is administered with capecitabine and/or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
  • a combination therapy as described herein is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
  • a combination therapy as described herein is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT- 11.
  • a combination therapy as described herein is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.
  • a combination therapy as described herein is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
  • a combination therapy as described herein is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma.
  • a combination therapy as described herein is administered in combination with gemcitabine, erlotinib, geftinib, and/or irinotecan to patients with non-small cell lung cancer.
  • a combination therapy as described herein is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.
  • a combination therapy as described herein is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy.
  • a combination therapy as described herein is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer.
  • a combination therapy as described herein is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.
  • a combination therapy as described herein is administered in combination with oblimersen to patients with small cell lung cancer.
  • a combination therapy as described herein is administered in combination with ABT-737 (Abbott Laboratories) and/or obatoclax (GXl 5-070) to patients with lymphoma and other blood cancers.
  • ABT-737 Abbott Laboratories
  • GXl 5-070 obatoclax
  • a combination therapy as described herein is administered alone or in combination with a secondary active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
  • a secondary active ingredient such as vinblastine or fludarabine
  • a combination therapy as described herein is administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) or dacarbazine, or a combination thereof, to patients with various types or stages of melanoma.
  • a combination therapy as described herein is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.
  • a combination therapy as described herein is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
  • cyclophosphamide IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.
  • a combination therapy as described herein is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin, vincristine and/or dexamethasone.
  • a combination therapy as described herein is administered to patients with relapsed or refractory multiple myeloma in combination with dexamethasone.
  • a combination therapy as described herein is administered to patients with multiple myeloma in combination with dexamethasone.
  • the combination includes lenalidomide, a PD-L1 inhibitor, and a proteasome inhibitor. The combination can further include dexamethasone.
  • the combination includes lenalidomide, dexamethasone, and durvalumab. In one embodiment, the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
  • a combination therapy as described herein is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
  • a combination therapy as described herein is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM- CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon, or a combination thereof.
  • a combination therapy as described herein is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
  • a combination therapy as described herein is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.
  • a combination therapy as described herein is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
  • a combination therapy as described herein is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
  • Also encompassed herein is a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to the patient (e.g., a human) combination therapy as described herein.
  • Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof.
  • the administration of a combination therapy as described herein in certain embodiments, alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti-cancer drug.
  • a compound provided herein as administered in a combination therapy as described herein is administered orally and daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient.
  • a compound provided herein as administered in a combination therapy as described herein is administered in combination with specific agents such as heparin, aspirin, Coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
  • a compound provided herein as administered in a combination therapy as described herein is administered to patients with diseases and disorders associated with or characterized by, undesired angiogenesis in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.
  • the methods of treating, preventing, and/or managing described hereinabove can include combination therapies described herein that are administered using cycling therapy as described herein.
  • Immunomodulatory agent and a checkpoint inhibitor for indications described herein The study will be conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practices (GCPs).
  • TILs Tumor-infiltrating lymphocytes
  • mAbs monoclonal antibodies
  • Blockade of immune-checkpoint inhibitors such as cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), PD-1, and PD-L1 have shown clinical activity not only in conventionally immune-responsive tumors such as melanoma and renal cell carcinoma but also in non-small cell lung cancer and prostate cancer.
  • Pembrolizumab and nivolumab are both PD-1 blocking antibodies and the first in the anti-PD-1 pathway family of checkpoint inhibitors to gain approval from the US Food and Drug Administration (FDA), pembrolizumab for melanoma and nivolumab for melanoma and squamous non-small cell lung cancer.
  • FDA US Food and Drug Administration
  • Both pembrolizumab and nivolumab have received European Commission regulatory approval for the treatment of metastatic melanoma.
  • the European Commission has also approved nivolumab for the treatment of advanced previously treated squamous NSCLC.
  • Nivolumab has gained approval for the treatment of melanoma in Japan.
  • Lymphomas and leukemias comprise multiple histologies. It is hypothesized without being bound by any particular theory that checkpoint inhibitors such as durvalumab have activity in multiple indications based on known expression pattern of PD-Ll/PD-1, available preclinical data, and recent clinical data utilizing nivolumab or pembrolizumab in relapsed refractory classical Hodgkin lymphoma and promising early data of pidilizumab alone or in combination with rituximab in diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL), respectively; also nivolumab monotherapy has shown antitumor activity in DLBCL, FL and T- cell lymphomas.
  • checkpoint inhibitors such as durvalumab have activity in multiple indications based on known expression pattern of PD-Ll/PD-1, available preclinical data, and recent clinical data utilizing nivolumab or pembrolizumab in re
  • the programmed cell death- 1 plays an important role in the regulation of the immune response.
  • the PD-1 receptor in conjunction with receptor ligands PD-L1 and PD-L2, functions to regulate the immune system primarily by down regulating signals of the T-cell receptor.
  • PD-Ll expressed on tumor cells binds to PD-1 on T-cells which leads to down- regulation of T-cell activity and allows tumor cells to evade the immune response.
  • an antibody that blocks the interaction between PD-Ll and its receptors can relieve PD-Ll -dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T-cells.
  • the levels of tumor-infiltrating lymphocytes, and more specifically cytotoxic T-cells, have been correlated with improved prognosis in a number of cancers including colorectal, melanoma, and lung.
  • an anti -PD-Ll antibody could be used therapeutically to enhance antitumor immune responses in multiple forms of cancer.
  • Lenalidomide and pomalidomide has pleiotropic activities including a capacity to activate K cells, to increase T-cell proliferation and function, and to enhance macrophage- mediated ADCC of rituximab-coated tumor cells.
  • the main molecular target of lenalidomide is the E3 ubiquitin ligase cereblon that was recently shown to trigger induction of cytokine production by T-cells.
  • T-cells display immunological synapse dysfunction with impaired F-actin polymerization and reduced effector function.
  • lenalidomide can repair the Rho A mediated T-cell synapse defect present in cancer patients thereby restoring T-cell functions and potentially enabling the effect of immunotherapies, lenalidomide and rituximab in relapsed, refractory and first line FL, based on Phase 2 results suggesting that this combination may be a reasonable alternative to traditional chemoimmunotherapy .
  • an administrative window of ⁇ 2 days for study Day 1 visits and ⁇ 1 for scheduled interim study visits (e.g., Day 18, 15, 22 visits) are allowed.
  • Subjects who receive lenalidomide should have at least a 7-day rest between two 21 -day treatment periods and therefore this should be taken into consideration when applying the visit window of ⁇ 2 days. If assessments are performed within 48 hours of Day 1 of each cycle, safety laboratory and physical examinations need not be repeated on Day 1. Treatment cycles are 28 days in duration. Efficacy Assessments. For lymphoma, disease response to treatment is determined by the Lugano Classification including a careful review of imaging and laboratory studies and clinical findings.
  • Integrated PET-CT is preferred for response assessment of FDG-avid lymphomas (e.g., DLBCL, HL, FL, transformed large cell lymphoma), while dedicated CT scan alone is preferred for FDG non-avid and variably FDG-avid histologies (e.g., CLL/SLL, MZL).
  • FDG-avid lymphomas e.g., DLBCL, HL, FL, transformed large cell lymphoma
  • dedicated CT scan alone is preferred for FDG non-avid and variably FDG-avid histologies (e.g., CLL/SLL, MZL).
  • CLL Minimal Residual Disease (Immunophenotyping of Blood for Circulating CLL Cells by Multiparameter Flow Cytometry) (CLL) If CBC with differential demonstrates the normalization of WBC to normal limits and no evidence of lymphocytosis, peripheral blood sample will be obtained (within 14 days) to determine the MRD status of the CLL in peripheral blood by multiparameter flow cytometry. In one section of the study, subjects receive:
  • All treatment cycles are 28 days.
  • Durvalumab infusion is administered before any other IP on the days which more than one investigational treatment should be given (e.g., Day 1 of Cycles 1 through 13), and then lenalidomide administration and rituximab infusion are recommended to follow, respectively.
  • Initial cohorts of 3 subjects are treated at varying dose levels. If one DLT occurs in the first 3-subject cohort at a dose level during the DLT observation period (i.e., from the time of the first IP dose through completion of Cycle 2), that cohort enrolls up to 6 subjects. Even in the absence of a DLT, additional subjects may be evaluated within a dose cohort if recommended by the SRC to adequately evaluate the safety or treatment effects of durvalumab in combination with lenalidomide and/or rituximab (depending on dose level). If dose level 1 is found to be the NTD, the next dose level may be explored.
  • Efficacy Analysis In the dose confirmation part and dose expansion part, treatment efficacy is evaluated by different histology cohorts for each treatment arm. Efficacy analysis is performed for particular treatment arm and subject histology cohort by combining data from both dose confirmation part and dose expansion part. Efficacy analysis is also performed separately for dose confirmation part and dose expansion part as well.
  • response evaluation is based on TvVG Response Criteria for Malignant Lymphoma (the Lugano Classification).
  • the overall response rate (ORR) is defined as the percent of subjects with best response of CR or PR.
  • Duration of response (DoR) is defined for responders only as the time from the first response (CR or PR) to
  • response evaluation will be based on TvVCLL guidelines for diagnosis and treatment of CLL.
  • the overall response rate (ORR) is defined as the percent of subjects with best response of CR, CRi, nPR, PR, or PRL.
  • Duration of response is defined for responders only as the time from the first response (CR, CRi, nPR, PR, or PRL) to disease progression or death. Overall survival is defined as the time from randomization until death from any cause.
  • Complete response is defined as absence of all detectable cancer after treatment.
  • Pathological complete response pCR
  • Partial response is defined as reduction of cancer by 30% or more.
  • duration of response is censored at the last date that the subject was known to be progression free. Duration of response is analyzed using the Kaplan- Meier method. Median duration of response along with two-sided confidence interval is provided for each treatment arm and subject histology cohort.
  • Progression-free survival is calculated as the time from first IP dose to the first documented progression or death due to any cause during the entire efficacy evaluation period.
  • Median PFS including 2-sided 95% CL is provided for each histology cohort within the same treatment arm.
  • Safety Analysis includes all subjects in the safety population.
  • Investigational product exposure is summarized for each treatment arm and histology cohort including duration of investigational product, total dose taken, and dose reductions.
  • Adverse events, vital sign measurements, clinical laboratory measurements, physical examination and concomitant medications is summarized by treatment arm and histology cohort.
  • Example 2 This example describes a Phase 1/2, open label, multicenter study is used to assess the safety and tolerability of durvalumab (anti-PD-Ll antibody) administered as a monotherapy and durvalumab administered in combination with lenalidomide, ibrutinib, rituximab, and
  • the open-label, multicenter, global study is designed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics of intravenous durvalumab in subjects with certain B- cell malignancies.
  • Approximately 253 patients may be enrolled in 4 treatment arms.
  • the treatment arms include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab.
  • the study includes 3 sections corresponding to dose finding, dose confirmation, and dose expansion.
  • the monotherapy treatment arm with durvalumab is not include a dose finding or dose expansion part.
  • Patients receiving monotherapy durvalumab may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect) upon progression of disease.
  • the primary endpoints of the study are (1) safety, (2) identification of recommended phase 2 dose (RP2D; phase 1, 3+3 design), and (3) preliminary overall response rate (ORR) measured by 2014 IWG criteria for lymphoma or 2008 IwCLL criteria for CLL.
  • NTD Non-Tolerated Dose
  • DLT Dose Limiting Toxicity
  • Maximum Tolerated Dose (MTD)- Phase is defined as the highest dose level below the NTD with 0 of 3 or 1 of 6 (i.e., ⁇ 1/3 of subjects) evaluable subjects experiencing DLTs during the DLT evaluation period.
  • Overall Response Rate - Phase 2 is defined as the percent of subjects with best response of complete response (CR) or partial response (PR).
  • Secondary Outcome Measures are defined as the percent of subjects with best response of complete response (CR) or partial response (PR).
  • Adverse events (AEs) of Phase 2 are coded according to Medical Dictionary for Drug Regulatory Activities (MedDRA) and classified using the NCI CTCAE. The incidence rates of AEs are tabulated by system organ class and preferred term. The incidence of AEs is also tabulated by severity within each system organ class and preferred term. The most severe grade of each preferred terms and adverse events of special interest for a subject are utilized for summaries of AEs by NCI CTCAE grade.
  • Duration of response (DoR)- Phasel/2 refers to the time from first Complete
  • CR Partial Response
  • PD progressive disease
  • PFS Progression free survival
  • IP Investigational product
  • Blood samples are collected to assay concentrations of durvalumab and other combination agents (i.e., lenalidomide or ibrutinib).
  • Cmax refers to the maximum observed concentration.
  • AUC refers to the area under the concentration-time curve.
  • Tmax refers to the time to maximum concentration, tl/2 refers to the terminal half-life.
  • V z /F refers to the volume of distribution.
  • Conditions for investigation include Lymphoma, Chronic B-Cell Lymphocytic Leukemia.
  • Durvalumab (MEDI4736) will be supplied by Celgene Corporation in single use vials in single count cartons. Each 10R vial will be supplied as a vialed liquid solution containing 500 mg (nominal) of durvalumab at a concentration of 50 mg/mL. Durvalumab should be stored in accordance with the product label.
  • Lenalidomide is supplied by Celgene Corporation in appropriate strengths for oral administration. Investigational product is supplied in high-density polyethylene (HDPE) bottles containing a 21 day supply of lenalidomide. Lenalidomide is stored in accordance to the product label.
  • HDPE high-density polyethylene
  • Rituximab is supplied outside the US and Canada by Celgene Corporation and labeled appropriately as investigational material for the study.
  • rituximab is obtained according to local clinical study agreement and in accordance with local guidelines and the approved rituximab label or Pharmacy Manual.
  • Ibrutinib is supplied outside the US and Canada by Celgene Corporation and labeled appropriately as investigational material for the study.
  • ibrutinib is obtained according to local clinical study agreement and in accordance with local guidelines and the approved Ibrutinib label (as 140 mg capsules) and the Pharmacy Manual.
  • Bendamustine is supplied outside the US or Canada by Celgene Corporation and labeled appropriately as investigational material for the study. For the US and Canada, bendamustine is obtained according to the local clinical study agreement and in accordance with local guidelines and the bendamustine lable and the Pharmacy Manual.
  • IFRT therapy may be added based on 2 Gy on each of 2 consecutive days to one tumor site in subjects who have with at least 1 measurable lesion (>1.5 cm and outside of the involved field which are irradiated) at the time of disease progression in Arm D (durvalumab monotherapy). This therapy is provided at the sites.
  • Arm A Durvalumab in combination with Lenalidomide and Rituximab: [00503] Subjects assigned to Arm A receive:
  • Lenalidomide (PO) is administered after the durvalumab infusions on the days (e.g., Day 1 of Cycles 1 through 13) when more than one IP should be given.
  • Lenalidomide 10 mg or 20 mg dose (depending on dose level in dose finding/confirmation part or renal function in dose expansion part) should be taken orally once daily, at approximately the same time each day. There is no requirement for taking lenalidomide with or without food, or with or without certain types of foods or liquids.
  • Lenalidomide doses are taken from Days 1 through 21 of 28-day cycle. A 7-day rest period is required. A rest period may be extended due to toxicity as needed.
  • Arm B Durvalumab in combination with Ibrutinib:
  • Ibrutinib (PO) continuous once daily until disease progression, unacceptable toxicity or discontinuation for any other reason • Ibrutinib (PO) administered after the durvalumab infusion on the days (e.g., Day 1 of Cycles 1 through 13) which both investigational treatments should be given.
  • Ibrutinib depending on dose level, 280 mg (2 x 140 mg capsules), 420 mg (3 x 140 mg capsules;) or 560 mg (4 x 140 mg capsules; is administered orally once daily with 8 ounces (approximately 240 mL) of water.
  • the capsules are swallowed intact and subjects should not attempt to open capsules or dissolve them in water.
  • Each dose of ibrutinib should be taken at least 30 minutes before eating or at least 2 hours after a meal, at approximately the same time each day.
  • Arm C Durvalumab in combination with Bendamustine and Rituximab: [00507] Subjects assigned to Arm C receive:
  • Bendamustine may be stopped after 4 cycles if the subject experiences a cumulative toxicity related to bendamustine and there is no clinical evidence of a favorable benefit to risk ratio for continuation of bendamustine treatment as per the investigator's medical judgment. If bendamustine is stopped earlier than 6 cycles, rituximab may be continued up to 6 cycles.
  • Bendamustine will be administered as a 30-minute IV infusion at a dose of 90 or 70 mg/m 2 (depending on dose level).
  • Rituximab dose is 375 mg/m 2 in all cycles for Non-Hodgkin lymphoma (NHL).
  • Rituximab dose is 375 mg/m 2 (Cycle 1; first dose) and 500 mg/m 2 (subsequent doses: Cycle 2 through 6) for Chronic lymphocytic leukemia (CLL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Provided herein are methods for treating, preventing, and/or managing hematological cancers by administering a combination therapy as described herein that optionally includes an immunomodulatory compound as described herein and a checkpoint inhibitor as described herein and a secondary active agent as described herein.

Description

COMBINATION THERAPY FOR TREATMENT OF HEMATOLOGICAL CANCERS
AND SOLID TUMORS
1 CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Nos. 62/233,960, filed September 28, 2016 and 62/307,314, filed March 11, 2016, the entireties of which are incorporated herein by reference and for all purposes.
2 FIELD
[0002] Provided herein are combination therapies and methods for treating, preventing, and/or managing hematological cancers and solid tumors using combination therapies that include at least one immunomodulatory compound as described herein and at least one checkpoint inhibitor as described herein. Also provided herein is a combination of at least one immunomodulatory compound and at least one checkpoint inhibitor for use in methods for treating, preventing, and/or managing hematological cancers and solid tumors.
3 BACKGROUND
[0003] Cancer can induce significant suppression of the immune system and escape from the immune surveillance mechanisms of the host. Dysregulation of host immune system is now considered one important hallmark of cancer (Hanahan et al, Cell, 2011, 144, 646-674). The interactions between cancer and the host immune system have been extensively studied and many types of immunotherapies have been explored for cancer treatment.
[0004] One class of immunotherapy is agents targeting specific checkpoint proteins that play critical roles in regulating T cell activation and proliferation. These proteins function as co- receptors on the surfaces of T cells and help regulate T cell responses following T cell activation (Wolchok et al., Cancer J, 2010, 16, 311-317). Two of the best characterized checkpoint proteins are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1). Both serve as negative regulators of T cell activation. T cell activation induces expression of CTLA-4 on T lymphocytes, thereby inhibits further T cell activation and proliferation. Furthermore, anti- CTLA-4 antibodies can directly activate CD4(+) and CD8(+) effector cells and generate antitumor responses (Wolchok et al., Oncologist, 2008, 13 (suppl 4), 2-9). Pre-clinical models showed anti-tumor activity of anti-CTLA-4 antibodies in many tumor types, and a phase III randomized trial has demonstrated overall survival benefit of the anti-CTLA-4 antibody ipilimumab in patients with advanced melanoma (Hodi et al., N. Engl. J. Med., 2010, 363, 711- 723). PD-1 signaling plays an important role in promoting regulatory T cell (Treg) function and preventing auto-immunity (Francisco et al, Immunol. Rev., 2010, 236, 219-242). Over- expression of PD-1 and its ligands, PD-L1 and PD-L2, has been found in many types of cancers and the over-expression was associated with advanced tumor stage and poor survival (Thompson et al, Cancer Res., 2006, 66, 3381-3385; Hamanishi et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 3360-3365). Blocking of PD-l/PD-1 ligand interaction by antibodies can inhibit Treg function, promote host immune response, and inhibit tumor growth in various cancer models (Tsushima et al, Blood, 2007, 110, 180-185; Iwai et al, Proc. Natl. Acad. Sci. USA, 2002, 99, 12293-12997). Early-phase clinical trials of anti-PD-1 antibodies have shown promising antitumor activity in solid cancers and hematological malignancies (Berger et al, Clin. Cancer Res., 2008, 14, 3044-3051; Ansell et al, N. Engl. J. Med, 2015, 372, 311-319). However, unlike in solid tumors there is paucity of data and scientific knowledge of the role of check point inhibition in MDS.
[0005] Thus, there is a need in the art for new treatments that reduce treatment failure and reduce or eliminate recurrence or development of resistance to anti-cancer agents.
4 SUMMARY
[0006] Provided herein, inter alia, are combination therapies that include an
immunomodulatory compound as described herein and one or more checkpoint inhibitors.
[0007] In one embodiment the immunomodulatory compound is 3-(4-amino-l-oxo-l ,3- dihy dro-i soindol-2-yl)piperidine-2, 6-dione .
[0008] In one embodiment the immunomodulatory compound is 4-(amino)-2-(2,6-dioxo(3- piperidyl))-isoindoline-l,3-dione.
[0009] In one embodiment the checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1/PD-L1 inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a B7 inhibitor, a T- cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an OX40 (CD 134) agonist, a GITR agonist, a CD 137 agonist, a CD40 agonist, and an IDO inhibitor. [0010] In one embodiment the checkpoint inhibitor comprises a CTLA-4 inhibitor.
[0011] In one embodiment the checkpoint inhibitor comprises tremelimumab or ipilimumab.
[0012] In one embodiment the checkpoint inhibitor comprises a PD-1 inhibitor.
[0013] In one embodiment the PD-1 inhibitor is selected from group consisting of nivolumab, pembrolizumab, CT-011, and AMP-224. In one embodiment the PD-1 inhibitor is nivolumab. In one embodiment the PD-1 inhibitor is pembrolizumab. In one embodiment the PD-1 inhibitor is CT-011. In one embodiment the PD-1 inhibitor is AMP-224.
[0014] In one embodiment the checkpoint inhibitor comprises a PD-L1 inhibitor.
[0015] In one embodiment the PD-L1 inhibitor selected from durvalumab or BMS-936559.
[0016] In one embodiment the PD-L1 inhibitor is durvalumab. In one embodiment the PD- Ll inhibitor is BMS-936559.
[0017] In one embodiment the checkpoint inhibitor comprises a PD-L2 inhibitor.
[0018] In one embodiment the checkpoint inhibitor comprises a LAG-3 inhibitor.
[0019] In one embodiment the LAG-3 inhibitor comprises IMP321 or BMS-986016.
[0020] In one embodiment the checkpoint inhibitor comprises a B7 inhibitor.
[0021] In one embodiment the checkpoint inhibitor comprises a B7-H3 inhibitor or a B7-H4 inhibitor.
[0022] In one embodiment the checkpoint inhibitor comprises T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor.
[0023] In one embodiment the checkpoint inhibitor comprises an OX40 (CD 134) agonist.
[0024] In one embodiment the OX40 agonist is selected from anti-OX-40 or MEDI6469.
[0025] In one embodiment the checkpoint inhibitor comprises GITR agonist.
[0026] In one embodiment the checkpoint inhibitor comprises CD137 agonist.
[0027] In one embodiment the CD137 agonist is selected from urelumab or PF-05082566.
[0028] In one embodiment the checkpoint inhibitor comprises CD40 agonist.
[0029] In one embodiment the checkpoint inhibitor comprises IDO inhibitor. [0030] In one embodiment the IDO inhibitor is selected from INCB024360 or indoximod.
[0031] In one embodiment the combination also includes a secondary active agent as described herein.
[0032] When the combination includes a secondary active agent described herein, the secondary active agent can be an antibody, such as for example rituximab, ibrutinib, or a combination of bendamustine/rituximab.
[0033] Further provided herein, inter alia, are combination therapies that include a checkpoint inhibitor in combination with one or more secondary active agents.
[0034] In one embodiment, the combination therapy includes a PD-L1 inhibitor described herein in combination with one or more secondary active agents.
[0035] In one embodiment the PD-L1 inhibitor is durvalumab.
[0036] In one embodiment the secondary active agent is ibrutinib. In one embodiment, the secondary active agent is rituximab. In one embodiment the secondary active agent is bendamustine. In one embodiment the secondary active agent is a combination of rituximab and bendamustine.
[0037] In one aspect is a method of treating, preventing, and/or managing solid tumors by administering to a patient in need thereof the combination therapy as described herein.
[0038] In one embodiment the solid tumor comprises cancer of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, or uterus.
[0039] In one embodiment the patient was treated with a prior treatment comprising a hypomethylating agent (HMA).
[0040] In one embodiment, the patient was treated with one or more of a proteasome inhibitor, an immunomodulatory agent, a histone deacetylase inhibitor (HDAC inhibitor) or an alkylating agent; or a combination thereof.
[0041] In one embodiment, the patient has previously received stem cell transplantion. In one embodiment, the stem cell transplantion is an autologous stem cell transplant. In one embodiment, the stem cell transplantion is allogeneic. In one embodiment, the stem cell transplantation comprises hematopoietic stem cell transplant, or peripheral blood stem cell transplant.
[0042] In one embodiment, the patient has not previously received stem cell transplantation.
[0043] In one embodiment the combination therapy reduces or eliminates minimal residual disease (MRD) state in said patient.
[0044] In one embodiment the combination therapy is administered after administration of chemotherapy. In one embodiment the combination therapy is administered before or during administration of chemotherapy.
[0045] In another aspect is a method of treating, preventing, and/or managing hematological cancer by administering to a patient in need thereof the combination therapy as described herein.
[0046] In one embodiment the hematological cancer is, non-Hodgkin's lymphoma (NHL), Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) B-cell lymphoma, MALT, lymhoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, adult T-cell lymphoma, Peripheral T-cell lymphoma, other B and T cell lymphoma/leukemias, and multiple myeloma.
[0047] In one embodiment the hematological cancer is chronic lymphocytic leukemia.
[0048] In one embodiment the patient has hematological cancer that is relapsed or refractory. In one embodiment the patient has cancer that is relapsed or refractory.
[0049] In one embodiment the patient was treated with a prior treatment comprising a hypomethylating agent (HMA).
[0050] In one embodiment the combination therapy reduces or eliminates minimal residual disease (MRD) state in the patient.
[0051] In one embodiment the combination therapy is administered after administration of chemotherapy.
[0052] In another aspect is a method of treating, preventing, and/or managing
myelodysplastic syndromes (MDS) by administering to a patient in need thereof the combination therapy described herein. [0053] In one embodiment the MDS advances to acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL).
[0054] In one embodiment the MDS is high risk MDS.
[0055] In one embodiment the AML is relapsed/refractory AML, trilineage dysplasia AML (AML-TLD), or therapy induced AML (tAML).
[0056] In one embodiment the patient has MDS that is relapsed or refractory.
[0057] In one embodiment the patient was treating with a prior treatment comprising a hypomethylating agent (HMA).
[0058] In one embodiment the combination therapy includes a compound described herein, a checkpoint inhibitor described herein, and optionally one or more secondary active agents described herein.
[0059] In one embodiment the combination therapy includes a checkpoint inhibitor as described herein in combination with one or more secondary active agents described herein.
[0060] In one embodiment the combination therapy includes a secondary active agent as described herein and reduces or eliminates minimal residual disease (MRD) state in said patient.
[0061] In one embodiment the combination therapy includes a secondary active agent as described herein and the combination is administered after administration of a previous chemotherapy.
[0062] In one embodiment the combination therapy is administered before or after a stem cell transplant (SCT).
[0063] In one embodiment the combination therapy is administered within 180 days of a SCT.
[0064] In one embodiment the combination therapy is administered after a donor lymphocyte infusion (DLI).
[0065] In one embodiment the administration of a combination therapy described herein reduces or eliminates the need for immunosuppressive drugs. [0066] In one embodiment the combination therapy prolongs complete remission of said MDS compared to treatment without said combination therapy.
[0067] In one embodiment the immunomodulatory compound of said combination therapy is administered daily for 21 consecutive days followed by a 7 day rest period in a 28 days cycle.
[0068] In one embodiment the checkpoint inhibitor is administered on one or more days in a 28 days cycle.
[0069] In one embodiment the checkpoint inhibitor is administered on day 1 of a 28 day cycle.
[0070] In one embodiment the checkpoint inhibitor is administered on day 1 of cycles 1 through 13.
[0071] In one embodiment the checkpoint inhibitor is a PD-L1 inhibitor.
[0072] In one embodiment the PD-L1 inhibitor is an anti-PD-Ll antibody.
[0073] In one embodiment the anti-PD-Ll antibody comprises durvalumab.
[0074] In one embodiment the 28 days cycle is repeated 1-12 times.
[0075] In one embodiment the combination therapy is administered to said patient until disease progression or unacceptable toxicity.
[0076] In one embodiment the method further comprises administering a secondary active agent.
[0077] In one embodiment the secondary active agent is administered weekly in a 28 days cycle. In one embodiment, administration of the secondary active agent is continuous without a rest period. In one embodiment, administration of the secondary active agent is stopped during a 7-day rest period in the cycle.
[0078] In one embodiment the secondary active agent is rituximab.
[0079] In one embodiment the immunomodulatory compound of said combination therapy is administered at an amount of about 0.5 to about 5 mg.
[0080] In one embodiment the immunomodulatory compound of said combination therapy is administered at an amount of about 1 to about 5 mg. [0081] In one embodiment the immunomodulatory compound of said combination therapy is administered at an amount of about 1 to about 25 mg.
[0082] In one embodiment the immunomodulatory compound of said combination therapy is administered at an amount of about 5 to about 25 mg.
[0083] In one embodiment the immunomodulatory compound is administered at about 10 mg or about 20 mg.
[0084] In one embodiment the checkpoint inhibitor is administered at an amount of about 500 mg to about 2000 mg.
[0085] In one embodiment the checkpoint inhibitor is administered at an amount of about 1500 mg.
[0086] In one embodiment the patient has been previously treated for cancer. In one embodiment the patient has not been previously treated for cancer.
[0087] In one embodiment the patient is non-responsive to at least one anti-cancer treatment.
[0088] In one embodiment the patient has a cancer that is resistance to at least one anticancer treatment.
[0089] In one embodiment the patient has undergone at least one surgery to treat said cancer.
[0090] In another aspect is a method for treating, preventing, and/or managing
relapsed/refractory multiple myeloma in patients with impaired renal function comprising administering a combination therapy as described herein.
[0091] In another aspect is a method for treating hepatocellular carcinoma (HCC) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0092] In another aspect is a method for treating a B-cell malignancy comprising
administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0093] In one embodiment, the B-cell malignancy is selected from the group consisting of mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B- cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), and modular lymphocyte pre-dominant Hodgkin lymphoma. In one embodiment, the B-cell malignancy is mantle cell lymphoma (MCL). In one embodiment, the B-cell malignancy is follicular lymphoma (FL). In one embodiment, the B-cell malignancy is chronic lymphocytic leukemia (CLL). In one embodiment, the B-cell malignancy is Burkitt lymphoma. In one embodiment, the B-cell malignancy is marginal-zone lymphoma (MZL) including splenic variants. In one embodiment, the B-cell malignancy is diffuse large B- cell lymphoma (DLBCL). In one embodiment, the B-cell malignancy is lymphoplasmacytic lymphoma (LPL). In one embodiment, the B-cell malignancy is multiple myeloma (MM). In one embodiment, the B-cell malignancy is classical type Hodgkin lymphoma (HL). In one embodiment, the B-cell malignancy is modular lymphocyte pre-dominant Hodgkin lymphoma. In one embodiment, the B-cell malignancy is multiple myeloma.
[0094] In another aspect is a method for treating a T-cell malignancy comprising
administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0095] In one embodiment, the T-cell malignancy is selected from the group consisting of peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, angioimunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, lymphoblastic lymphoma, treatment related T-cell lymphoma; T-cell NHL, or chronic T-cell lymphoma. In one embodiment, the T-cell malignancy is peripheral T-cell lymphoma (not otherwise specified). In one embodiment, the T-cell malignancy is analplastic large cell lymphoma. In one embodiment, the T-cell malignancy is Sezary syndrome. In one embodiment, the T-cell malignancy is primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. In one embodiment, the T-cell malignancy is angioimunoblastic lymphoma. In one embodiment, the T-cell malignancy is cutaneous T-cell lymphoma. In one embodiment, the T-cell malignancy is adult T-cell leukemia/lymphoma (ATLL). In one embodiment, the T-cell malignancy is blastic NK-cell lymphoma. In one embodiment, the T-cell malignancy is lymphoblastic lymphoma. In one embodiment, the T-cell malignancy is treatment related T-cell lymphoma. In one embodiment, the T-cell malignancy is T-cell NHL. In one embodiment, the T-cell malignancy is chronic T-cell lymphoma. [0096] In another aspect is a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0097] In another aspect is a method for treating lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0098] In another aspect is a method for treating non-Hodgkin lymphoma (NHL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[0099] In one embodiment the combination includes administering a secondary active agent as described herein.
[00100] In one embodiment the secondary active agent is rituximab, ibrutinib, or a
combination of bendamustine/rituximab.
[00101] In another aspect is a method for treating locally advanced or metastatic transitional cell bladder cancer in a patient in need thereof, said method comprising administering a combination therapy as described herein in combination with gemcitabine and cisplatinum.
[00102] In another aspect is a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
[00103] In another aspect is a method for treating lymphoma as described herein comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
[00104] In another aspect is a method for treating pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma, said method comprising administering to said pediatric patient a combination therapy as described herein in combination with
temozolomide.
[00105] In another aspect is a method for treating relapsed or progressive CNS cancer, said method comprising administering a combination therapy as described herein in combination with celecoxib, etoposide and cyclophosphamide. [00106] In another aspect is a method for treating patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms, said method comprising
administering a combination therapy as described herein in combination with temodar.
[00107] In another aspect is a method for treating patients with recurrent glioblastoma, said method comprising administering a combination therapy as described herein in combination with irinotecan.
[00108] In another aspect is a method for treating pediatric patients with brain stem glioma, said method comprising administering a combination therapy as described herein in combination with carboplatin.
[00109] In another aspect is a method for treating pediatric patients with progressive malignant gliomas, said method comprising administering a combination therapy as described herein in combination with procarbazine.
[00110] In another aspect is a method for treating patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms , said method comprising administering a combination therapy as described herein in combination with cyclophosphamide.
[00111] In another aspect is a method for treating high grade recurrent malignant gliomas, said method comprising administering a combination therapy as described herein in combination with Gliadel®.
[00112] In another aspect is a method for treating anaplastic astrocytoma, said method comprising administering a combination therapy as described herein in combination with temozolomide and tamoxifen.
[00113] In another aspect is a method for treating gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma, said method comprising administering a combination therapy as described herein in combination with topotecan.
[00114] In another aspect is a method for treating patients with metastatic breast cancer, said method comprising administering a combination therapy as described herein in combination with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, or PLX3397 (Plexxikon); or a combination thereof.
[00115] In another aspect is a method for treating neuroendocrine tumors, said method comprising administering a combination therapy as described herein in combination with temozolomide.
[00116] In another aspect is a method for treating patients with recurrent or metastatic head or neck cancer, said method comprising administering a combination therapy as described herein in combination with gemcitabine.
[00117] In another aspect is a method for treating patients with pancreatic cancer, said method comprising administering a combination therapy as described herein in combination with gemcitabine.
[00118] In another aspect is a method for treating patients with colon cancer, said method comprising administering a combination therapy as described herein in combination ARISA®, avastatin, taxol, and/or taxotere.
[00119] In another aspect is a method for treating patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma, said method comprising administering a combination therapy of any one of claims 1 in combination with capecitabine and/or PLX4032 (Plexxikon).
[00120] In another aspect is a method for treating refractory colorectal cancer, said method comprising administering a combination therapy as described herein in combination with capecitabine, xeloda, and/or CPT-11.
[00121] In another aspect is a method for treating patients with refractory colorectal cancer or patients with unresectable or metastatic colorectal carcinoma, said method comprising administering a combination therapy as described herein in combination with capecitabine and irinotecan.
[00122] In another aspect is a method for treating patients with unresectable or metastatic hepatocellular carcinoma, said method comprising administering a combination therapy as described herein in combination with interferon alpha or capecitabin. [00123] In another aspect is a method for treating patients with primary or metastatic liver cancer, said method comprising administering a combination therapy as described herein in combination with cisplatin and thiotepa.
[00124] In another aspect is a method for treating patients with refractory or relapsed or high- risk acute myelogenous leukemia, said method comprising administering a combination therapy as described herein in combination with fludarabine, carboplatin, and/or topotecan.
[00125] In another aspect is a method for treating patients with unfavorable karotype acute myeloblastic leukemia, said method comprising administering a combination therapy as described herein in combination with liposomal daunorubicin, topotecan and/or cytarabine.
[00126] In another aspect is a method for treating patients with non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with gemcitabine, abraxane, erlotinib, geftinib, and/or irinotecan.
[00127] In another aspect is a method for treating patients with non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with carboplatin and irinotecan.
[00128] In another aspect is a method for treating patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy, said method comprising administering a combination therapy as described herein in combination with doxetaxol.
[00129] In another aspect is a method for treating patients with non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy.
[00130] In another aspect is a method for treating patients with stage MB or IV non-small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with taxotere.
[00131] In another aspect is a method for treating patients with small cell lung cancer, said method comprising administering a combination therapy as described herein in combination with oblimersen. [00132] In another aspect is a method for treating patients with lymphoma and other blood cancers, said method comprising administering a combination therapy as described herein in combination with ABT-737 and/or obatoclax.
[00133] In another aspect is a method for treating patients with various types of lymphoma, said method comprising administering a combination therapy as described herein in combination with vinblastine or fludarabin.
[00134] In another aspect is a method for treating patients with Hodgkin's lymphoma, non- Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma, said method comprising administering a combination therapy as described herein.
[00135] In another aspect is a method for treating patients with melanoma, said method comprising administering a combination therapy as described herein in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine.
[00136] In another aspect is a method for treating patients with malignant mesothelioma, or stage MB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome, said method comprising administering a combination therapy as described herein in combination with vinorelbine.
[00137] In another aspect is a method for treating multiple myeloma, said method comprising administering a combination therapy as described herein in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, a proteasome inhibitor, or a combination thereof.
[00138] In another aspect is a method for treating patients with relapsed or refractory multiple myeloma, said method comprising administering a combination therapy as described herein in combination with doxorubicin, vincristine and/or dexamethasone. In one embodiment, the method is a method of treating patients having relapsed or refractory multiple myeloma by administering a combination therapy described herein in combination with dexamethasone.
[00139] In another aspect is a method for treating patients with ovarian cancer, said method comprising administering a combination therapy as described herein in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
[00140] In another aspect is a method for treating patients with prostate cancer, said method comprising administering a combination therapy as described herein in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine,
dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon, or a combination thereof.
[00141] In another aspect is a method for treating patients with renal cell cancer, said method comprising administering a combination therapy as described herein in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
[00142] In another aspect is a method for treating patients with gynecologic, uterus or soft tissue sarcoma cancer, said method comprising administering a combination therapy as described herein in combination with IFN, a COX-2 inhibitoror, sulindac, or a combination thereof.
[00143] In another aspect is a method for treating patients with a solid tumor, said method comprising administering a combination therapy as described herein in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
[00144] In another aspect is a method for treating patients with scleroderma or cutaneous vasculitis, said method comprising administering a combination therapy as described herein in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
5 DETAILED DESCRIPTION
5.1. Definitions
[00145] All patents, applications, published applications and other publications are
incorporated by reference in their entirety. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Headings used herein are for organizational purposes only and in no way limit the invention described herein.
[00146] As used herein, "administer" or "administration" refers to the act physically delivering a substance as it exists outside the body into a patient, such as by oral, mucosal, intradermal, intravenous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art. When a disease, disorder or condition, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof. When a disease, disorder or condition, or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.
[00147] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, a subject can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkey and human). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) having a disease, disorder or condition described herein. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing a disease, disorder or condition described herein.
[00148] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
[00149] Hematological cancer as used herein refers to blood-borne tumors (e.g., multiple myeloma, lymphoma and leukemia).
[00150] "Tumor" and "solid tumor" as used herein, refer to all lesions and neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. Other exemplary cancers are provided elsewhere herein. "Neoplastic," as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells having dysregulated or unregulated cell growth.
[00151] "Multiple myeloma" or "MM" is a cancer of plasma cells in the bone marrow.
Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common hematological malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin. M-protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by the myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.
[00152] Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast stimulating factors (including IL-1, IL-6 and TNF) which cause calcium to be leached from bones causing lytic lesions; hypercalcemia is another symptom. The osteoclast stimulating factors, also referred to as cytokines, may prevent apoptosis, or death of myeloma cells. Fifty percent of patients have radiologically detectable myeloma-related skeletal lesions at diagnosis. Other common clinical symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.
[00153] An improvement in the cancer or cancer-related disease can be characterized as a complete or partial response. "Complete response" or "CR" refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. "Partial response" refers to at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions.
[00154] A "sarcoma" is a solid tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Exemplary sarcomas that can be treated, prevented, and/or managed using the compositions and methods described herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
[00155] A "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that can be treated with the compositions and methods described herein include, adenocarcimonas, colorectal carcinoma, colorectal adenocarcinoma, acinar carcinoma, lung carcinoma, alveolar cell carcinoma, basal cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, chorionic carcinoma, colloid carcinoma, corpus carcinoma, cribriform carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lymphoepithelial carcinoma, nasopharyngeal carcinoma, papillary carcinoma, renal cell carcinoma of kidney, scirrhous carcinoma, small-cell carcinoma, spheroidal cell carcinoma, squamous carcinoma, squamous cell carcinoma, carcinoma telangiectaticum, and verrucous carcinoma.
[00156] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" refer to an action that occurs while a patient has a disease, disorder or condition described herein. "Treat," "treatment" and "treating" also refer to the reduction or amelioration of the progression, severity, and/or duration of a disease, disorder or condition described herein resulting from the administration of one or more therapies.
[00157] The term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual cancer cells (e.g., leukemia or lymphoma cells) in their lymphatic system, blood and/or blood forming tissues (e.g., marrow).
[00158] As used herein, and unless otherwise specified, the terms "manage," "managing" and "management" refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. In certain cases, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder. In certain embodiments, a subject is administered one or more therapies to "manage" a disease, disorder or condition, or one or more symptoms thereof, so as to prevent the progression or worsening of the disease, disorder or condition.
[00159] As used herein, unless otherwise specified, the term "preventing" refers to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of cancer and/or other disorders described herein. The term "prevention" includes the inhibition or reduction of a symptom of the particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment."
[00160] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to inhibit or reduce a symptom of a disease or to prevent recurrence of a disease. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the inhibition or reduction of a symptom of a disease or recurrence of a disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
[00161] The term "effective amount" as used herein refers to the amount of a therapy (e.g., a composition provided herein) which is sufficient to reduce and/or ameliorate the severity and/or duration of a given disease, disorder or condition and/or a symptom related thereto. This term also encompasses an amount necessary for the reduction or amelioration of the advancement or progression of a given disease, disorder or condition, reduction or amelioration of the recurrence, development or onset of a given disease, disorder or condition, and/or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy. In some embodiments, "effective amount" as used herein also refers to the amount of therapy provided herein to achieve a specified result. [00162] As used herein, and unless otherwise specified, the term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a cancer, or to delay or minimize one or more symptoms associated with the presence of the cancer. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the cancer. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of cancer, or enhances the therapeutic efficacy of another therapeutic agent.
[00163] As used herein, the term "therapy" refers to any protocol, method and/or agent that can be used in the prevention, management, treatment and/or amelioration of a given disease, disorder or condition. In certain embodiments, the terms "therapies" and "therapy" refer to a drug therapy, biological therapy, supportive therapy, and/or other therapies useful in the prevention, management, treatment and/or amelioration of a given disease, disorder or condition known to one of skill in the art such as medical personnel.
[00164] The term "pharmaceutically acceptable" as used herein means being approved by a regulatory agency of the Federal or state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
[00165] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. In one embodiment, suitable are hydrochloric, hydrobromic, phosphoric, and sulfuric acids.
[00166] As used herein, the terms "immunomodulatory compound," "immunomodulatory agent," "compound," and "immunomodulatory drug" refer generally to a molecule or agent capable of altering the immune response in some way. Non-limiting examples of
immunomodulatory compounds include those disclosed in Section 5.2.1 below.
[00167] As used herein, and unless otherwise specified, the term "stereoisomer" encompasses all enantiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds provided herein.
[00168] As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
[00169] As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70%) by weight, or greater than about 80% by weight of one stereoisomer of a compound.
[00170] As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having one chiral center. [00171] As used herein, unless otherwise specified, the terms "antibody" means a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen. Antibodies provided herein include, but are not limited to, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies, antibody mimetics, chimeric antibodies, humanized antibodies, human antibodies, antibody fusions, antibody conjugates, single chain antibodies, antibody derivatives, antibody analogues and fragments thereof, respectively. Also included are immunological fragments of an antibody (e.g., a Fab, a Fab', a F(ab')2, or a scFv), irrespective of whether such antibodies are produced, in whole or in part, via immunization, through recombinant technology, by way of in vitro synthetic means, or otherwise.
[00172] As used herein, unless otherwise specified, the term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%,40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[00173] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
[00174] The practice of the embodiments provided herein will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, and immunology, which are within the skill of those working in the art. Such techniques are explained fully in the literature. Examples of particularly suitable texts for consultation include the following:
Sambrook et al. (1989) Molecular Cloning; A Laboratory Manual (2d ed.); D.N Glover, ed. (1985) DNA Cloning, Volumes I and II; M.J. Gait, ed. (1984) Oligonucleotide Synthesis; B.D. Hames & SJ. Higgins, eds. (1984) Nucleic Acid Hybridization; B.D. Hames & S.J. Higgins, eds. (1984) Transcription and Translation; R.I. Freshney, ed. (1986) Animal Cell Culture;
Immobilized Cells and Enzymes (IRL Press, 1986); Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Scopes (1987) Protein Purification: Principles and Practice (2d ed.; Springer Verlag, N.Y.); and D.M. Weir and C. C. Blackwell, eds. (1986) Handbook of Experimental Immunology, Volumes I-IV.
5.2. Combination Therapies
[00175] Provided herein are combination therapies useful in the treatment, prevention, and management of cancer - particularly hematological cancers and solid tumors as described herein. Combination therapies described herein can include one or more immunomodulatory compounds and one or more checkpoint inhibitors (CPIs). In other embodiments, combination therapies described herein include one or more CPIs in combination with one or more secondary active agents. Also provided herein are combinations of at least one immunomodulatory compound and at least one checkpoint inhibitor for use in a method of treatment, prevention, and management of cancer - particularly hematological cancers and solid tumors as described herein.
5.2.1. Immunomodulatory Compounds
[00176] In one embodiment the immunomodulatory agent is lenalidomide. Lenalidomide has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma (MM) in combination with dexamethasone; transfusion-dependent anemia due to low- or intermediate- 1 -risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities; and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
[00177] In one embodiment the immunomodulatory agent is Pomalidomide. Pomalidomide is currently approved by the FDA for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
[00178] The inflammatory cytokine TNF-a, which is produced by macrophages and monocytes during acute inflammation, causes a diverse range of signaling events within cells. Without being limited by a particular theory, one of the biological effects exerted by the immunomodulatory compounds disclosed herein can be the reduction of myeloid cell TNF-a production. Immunomodulatory compounds disclosed herein may enhance the degradation of TNF-a mRNA.
[00179] Further, without being limited by theory, immunomodulatory compounds disclosed herein may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds disclosed herein may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds may have anti-inflammatory properties against myeloid cell responses, yet efficiently co-stimulate T cells to produce greater amounts of IL-2, IFN-γ, and to enhance T cell proliferation and CD8+ T cell cytotoxic activity. Further, without being limited by a particular theory, immunomodulatory compounds disclosed herein may be capable of acting both indirectly through cytokine activation and directly on Natural Killer ("NK") cells and Natural Killer T ("NKT") cells, and increase the NK cells' ability to produce beneficial cytokines such as, but not limited to, IFN-γ, and to enhance NK and NKT cell cytotoxic activity.
[00180] The immunomodulatory compounds disclosed herein contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. Thus, also provided herein is the use of stereomerically pure forms of the immunomodulatory compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds may be used. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33 :2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds
(McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical
Resolutions p. 268 (E L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
[00181] Immunomodulatory compounds provided herein include, but are not limited to, 1- oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Patent no. 5,635,517 which is incorporated herein by reference. These compounds have the structure I:
Figure imgf000026_0001
I
and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
one of X and Y is C=0, the other of X and Y is C=0 or CH2, and R2 is hydrogen or lower alkyl, in particular methyl. Exemplary immunomodulatory compounds of formula I include, but are not limited to:
l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
Figure imgf000026_0002
l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and and optically pure isomers thereof. In one embodiment, the immunomodulatory agents described herein include pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereiosmers thereof. In one embodiment,
immunomodulatory agents described herein include pharmaceutically acceptable salts thereof. In one embodiment, the immunomodulatory agents described herein do not include
pharmaceutically acceptable salts thereof.
[00182] Such compounds can be obtained via standard, synthetic methods (see e.g., United States Patent No. 5,635,517, incorporated herein by reference). The compounds are also available from Celgene Corporation, Warren, NJ.
[00183] Immunomodulatory agents include but are not limited to pomalidomide and lenalidomide. Lenalidomide has the following structure:
Figure imgf000027_0001
including an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In one embodiment, the compound is amorphous 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione. In one embodiment, the compound is srystalline solid form of 3-(4-amino-l-oxo-l ,3-dihydro- isoindol-2-yl)piperidine-2,6-dione, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, or Form H (see U.S. Patent No. 7,465,800 incorporated herein by reference). In one embodiment, the immunomodulatory agent is lenalidomide and not a pharmaceutically acceptable salt thereof. In one embodiment, the immunomodulatory agent is a hydrate of lenalidomide.
[00184] Lenalidomide can be prepared as described in WO2012/ 149299, the disclosure of which is incorporated herein by reference in its entirety. The compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
[00185] Lenalidomide can be prepared as described in WO2012/ 149299, the disclosure of which is incorporated herein by reference in its entirety. The compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
[00186] Pomalidomide has the following structure:
Figure imgf000027_0002
including an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In one embodiment, the immunomodulatory agent is a hydrate of pomalidomide.
[00187] The compounds described herein may be small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides,
oligosaccharides or other macromolecules. 5.2.2. Checkpoint Inhibitors
[00188] Combination therapies described herein include one or more checkpoint inhibitor(s) optionally administered in combination with compounds described herein in connection with methods provided herein. In one embodiment, combination therapies described herein include one checkpoint inhibitor administered in combination with a compound described herein. In another embodiment, combination therapies described herein include two checkpoint inhibitors administered in combination with a compound described herein. In yet another embodiment, combination therapies described herein include three or more checkpoint inhibitors administered in combination with a compound described herein in connection with methods provided herein. In still another embodiment combination therapies described herein include one checkpoint inhibitor described herein administered in combination with two compounds described herein. In still another embodiment combination therapies described herein include one checkpoint inhibitor administered in combination with one or more secondary active agents described herein. Also contemplated herein is administration of one or more checkpoint inhibitors administered in combination with one or more compounds described herein and a second therapeutic agent as described herein. In a particular embodiment combination therapies described herein include lenalidomide or pomalidomide administered in combination with one or more checkpoint inhibitors.
[00189] As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins. Without being limited by a particular theory, checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 72, 252-264). These proteins appear responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
[00190] In one aspect, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207, 157; 6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein in their entireties. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti- CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name Yervoy™. Accordingly, provided herein are combination therapies that include one or more CTLA-4 inhibitors and a compound as described herein. In certain instances, the combination therapy includes tremelimumab (ticilimumab or CP-675,206) and a compound as described herein. The combination therapy can include ipilimumab (MDX-010 or MDX-101) and a compound as described herein. Such combination therapies can include CTLA-4 inhibitors and compounds described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a CTLA-4 inhibitor include those as set forth herein, including for example lenalidomide or pomalidomide.
[00191] In another aspect, the checkpoint inhibitor is a PD-1/PD-L1 inhibitor. Examples of PD-1/PD-L1 inhibitors include, but are not limited to, those described in US Patent Nos.
7,488,802; 7,943,743; 8,008,449; 8, 168,757; 8,217, 149, and PCT Patent Application Publication Nos. WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated herein in their entireties.
[00192] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is nivolumab (also known as ONO-4538, BMS-936558, or MDX1106) or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is CT- 011, a humanized antibody. CT-011 administered alone has failed to show response in treating AML at relapse. In yet another embodiment, the anti-PD-1 antibody is AMP -224, a fusion protein. [00193] Accordingly, provided herein are combination therapies that include a PD-1 inhibitor and a compound as described herein. In one embodiment is a combination therapy that includes an anti-PD-1 antibody and a compound as described herein. In another embodiment is a combination therapy that includes nivolumab (ONO-4538, BMS-936558, and MDXl 106) and a compound as described herein. In yet another embodiment is a combination therapy that includes pembrolizumab and a compound as described herein. In still another embodiment is a combination therapy that includes CT-011 and a compound as described herein. In yet another embodiment is a combination therapy that includes AMP-224 and a compound as described herein. Such embodiments that include PD-1 inhibitors and compounds as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a PD-1 inhibitor or antibody include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00194] In another aspect, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody. In one embodiment, the anti-PD-Ll antibody is durvalumab (MEDI4736). In another embodiment, the anti-PD-Ll antibody is BMS-936559 (also known as MDX-1105-01). Accordingly, provided herein are combination therapies that include a PD-L1 inhibitor and a compound as described herein. In one embodiment is a combination therapy that includes durvalumab and a compound as described herein. In another embodiment is a combination therapy that includes BMS-936559 (MDX-1105-1) and a compound as described herein. Such embodiments include PD-L1 inhibitors and compounds as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a PD-L1 inhibitor include, but are not limited to, lenalidomide or pomalidomide. In another embodiment, the combination includes a PD-L1 antibody such as durvalumab and a compound described herein such as lenalidomide or pomalidomide. In still another embodiment, the combination includes a PD-L1 antibody such as durvalumab in combination with one or more secondary active agents described herein.
[00195] In still another aspect, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD- L2 antibody is rHIgM12B7A. Thus, provided herein are combination therapies that include an anti-PD-L2 inhibitor as described herein and a compound as described herein. In one
embodiment is a combination therapy that includes rHIgM12B7A and a compound as described herein. Such embodiments include PD-L2 inhibitors and compounds as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a PD-L2 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00196] In still another aspect, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al, J. Immunol, 2007, 179, 4202-4211). In another embodiment, the LAG- 3 inhibitor is BMS-986016. Thus, provided herein are combination therapies that include a LAG- 3 inhibitor as described herein and a compound as described herein. In one embodiment is a combination therapy that includes IMP321 and a compound as described herein. In another embodiment is a combination therapy that includes BMS-986016 and a compound as described herein. Such embodiments include LAG-3 inhibitors and compounds as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a LAG-3 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00197] In yet another aspect, the checkpoint inhibitors is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834). Thus, provided herein are combination therapies that include a B7 inhibitor and a compound described herein. In one embodiment is a combination therapy that includes B7-H3 inhibitor as described herein and a compound as described herein. In another embodiment is a combination therapy that includes a B7-H4 inhibitor as described herein and a compound as described herein. In still another embodiment is a combination therapy that includes MGA271 and a compound as described herein. Such embodiments include a B7 inhibitor as described herein and a compound as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a B7 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00198] In another aspect, the checkpoint inhibitors is a TIM-3 (T-cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86;
Sakuishi et al, J. Exp. Med, 2010, 207, 2187-94). Accordingly, in one embodiment is a combination therapy that includes a TIM-3 inhibitor and a compound as described herein, at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a TIM-3 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00199] In another aspect, the checkpoint inhibitor is an OX40 (CD 134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti- OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469. Accordingly, in one embodiment is a combination therapy that includes an OX40 agonist and a compound as described herein. In another embodiment is a combination therapy that includes an anti-OX40 antibody and a compound a described herein. In still another embodiment is a combination therapy that includes anti-OX-40 and a compound as described herein. In yet another embodiment is a combination therapy that includes MEDI6469 and a compound as described herein. Such embodiments include OX40 agonists and compounds, as described herein, at concentrations and amounts as set forth herein. Compounds useful in combination therapies including an OX40 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00200] In still another aspect, the checkpoint inhibitor is a GITR agonist. In one
embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti- GITR antibody is TRX518. Thus provided herein are combination therapies that include a GITR agonist and a compound as described herein. In one embodiment is a combination therapy that includes an anti-GITR antibody and a compound as described herein. In another embodiment is a combination therapy that includes TRX518 and a compound as described herein. Such embodiments include GITR agonists and compounds, as described herein, at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a GITR inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00201] In yet another aspect, the checkpoint inhibitor is a CD137 agonist. In one
embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti- CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566. Provided herein are combination therapies that include a CD137 agonist and a compound as described herein. In one embodiment is a combination therapy that includes an anti-CD 137 antibody and a compound as described herein. In another embodiment is a combination therapy that includes urelumab and a compound as described herein. In still another embodiment is a combination therapy that includes PF-05082566 and a compound as described herein. Such embodiments include CD137 agonists and compounds, as described herein, at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a CD 137 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00202] In another aspect, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893. Provided herein are combination therapies that include a CD40 agonist and a compound as described herein. In one embodiment is a combination therapy that includes an anti-CD40 antibody and a compound as described herein. In another embodiment is a combination therapy that includes CF-870,893 and a compound as described herein. Such embodiments include CD40 agonists and compounds, as described herein, at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a CD40 inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00203] In yet another aspect, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15). Thus, in one embodiment is a combination therapy that includes rhIL-15 and a compound as described herein at concentrations and amounts as set forth herein. Compounds useful in combination therapies including a rhIL-15 include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00204] In another aspect, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod. Thus provided herein are combination therapies that include an IDO inhibitor as described herein and a compound as described herein. In one embodiment is a combination therapy that includes INCB024360 and a compound as described herein. In another embodiment is a combination therapy that includes indoximod and a compound as described herein. Such embodiments include an IDO inhibitor and a compound, as described herein, in concentrations and amounts as set forth herein. Compounds useful in combination therapies including an IDO inhibitor include those as set forth herein include, but are not limited to, lenalidomide or pomalidomide.
[00205] In certain embodiments the above described combination therapies include lenalidomide and/or pomalidomide as described herein at concentrations and amounts as set forth herein. Likewise, it should be understood that combination therapies as described herein can include two or more of the checkpoint inhibitors described herein (including checkpoint inhibitors of the same or different class). Moreover, the combination therapies described herein can be used in combination with secondary active agents as described herein where appropriate for treating diseases described herein and understood in the art.
5.3. Administration of Combination Therapies
[00206] Combination therapies as described herein are administered without restriction on the order in which therapies are administered to a patient with a disease or disorder described herein. Thus, in one embodiment, a first therapy (e.g., a compound as described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a checkpoint inhibitor as described herein) to the subject. In another embodiment, a first therapy (e.g., a checkpoint inhibitor as described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a compound as described herein) to the subject.
[00207] In still another embodiment, a CPI as described herein (e.g. durvalumab) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a secondary active agent as described herein to the subject. In yet another embodiment, a secondary active agent as described herein can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a CPI (e.g. durvalumab) as described herein to the subject.
[00208] Administration can be performed using cyclic administration as described herein. Triple therapy is also contemplated herein (e.g., addition of a second compound or a second checkpoint inhibitor as described herein, addition of one or more secondary active agents as described herein or addition of another combination therapy as described herein).
[00209] Administration of the components of a combination therapy as described herein can occur simultaneously or sequentially as described above by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the cancer being treated.
[00210] The route of administration of a compound provided herein is independent of the route of administration of a checkpoint inhibitor as described herein. In one embodiment, lenalidomide and/or pomalidomide is administered orally (PO). In another embodiment, a compound provided herein is administered intravenously (IV). In certain embodiments, a CPI described herein is administered intravenously. In certain embodiments, a CPI described herein is administered in accordance with a package insert. The term "package insert" refers to instructions customarily included in commercial packages of medicaments approved by the FDA or a similar regulatory agency of a country other than the USA, which contains information about, for example, the usage, dosage, administration, contraindications, and/or warnings concerning the use of such medicaments. In certain embodiments, a secondary active agent described herein can be administered, for example, orally or intravenously. In one embodiment, a secondary active agent used in a combination described herein is administered in accordance with a package insert.
[00211] Thus, in accordance with these embodiments, a combination described herein can include a compound provided herein (e.g., lenalidomide or pomalidomide) where the compound is administered orally, and the second therapy (e.g. a checkpoint inhibitor described herein) can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, a compound provided herein (e.g., lenalidomide or pomalidomide) and a checkpoint inhibitor provided herein are administered by the same mode of administration, e.g., orally (PO) or by IV. In another embodiment, a compound provided herein (e.g., lenalidomide or pomalidomide) is administered by one mode of administration, e.g., orally, whereas a checkpoint inhibitor provided herein is administered by another mode of administration, e.g., IV.
[00212] Also in accordance with the embodiments described above, a combination described herein can include a CPI where the CPI is administered intravenously, and one or more secondary active agents described herein where the secondary active agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, a checkpoint inhibitor provided herein and a secondary active agent described herein are administered by the same mode of administration, e.g., IV. In another embodiment, a checkpoint inhibitor provided herein is administered by one mode of administration, e.g., by IV, whereas a secondary active agent provided herein is administered by at least one different mode of administration, e.g., PO.
5.4. Combination with Secondary Active Agents [00213] Certain combination therapies described herein can also be combined or used in combination with other therapeutic agents (e.g., secondary active agents) useful in the treatment and/or prevention of cancer described herein. Such therapies can be referred to herein as "triple therapies."
[00214] When used in this context, the term "in combination" includes the use of a
combination therapy as described herein with one or more secondary active agents (e.g., prophylactic and/or therapeutic agents) described herein. Administration of a secondary active agent in combination with a combination therapy as described herein does not restrict the order in which any of therapies are administered to a patient with a disease or disorder. Accordingly, a first therapy and a second therapy can be administered as set forth above and one or more secondary active agents can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
administration of either of the agents in the combination therapy.
[00215] Administration of secondary active agents is independent of the route of
administration for the combination therapies described herein, including each component (e.g., a compound described herein or checkpoint inhibitor described herein). The suitability of a particular route of administration employed for a particular secondary active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream), the cancer being treated, and patient tolerance. In certain instances the secondary active agent is administered in accordance with a package insert.
[00216] The secondary active agent can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form). In certain embodiments a secondary active agent is administered orally or by IV. In some embodiments, the secondary active agent is formulated together with a combination therapy as described herein. Such formulations include those set forth herein and can be supplied as components of kits described herein.
[00217] Secondary active agents can include anti-cancer agents. Exemplary secondary active agents include, but are not limited to: ace-11; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine;; docetaxel;
doxorubicin; doxorubicin hydrochloride; enloplatin; etoposide; etoposide phosphate; etoprine; floxuridine; fludarabine phosphate; fluorouracil; gemcitabine; gemcitabine hydrochloride;
herceptin; hydroxyurea; ibrutinib; idarubicin hydrochloride; irinotecan; irinotecan hydrochloride; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; mycophenolic acid; rituximab; romidepsin; spiromustine; spiroplatin; stem cell treatments such as PDA-001;
streptonigrin; streptozocin; sulofenur; teloxantrone hydrochloride; thiamiprine; thioguanine; uracil mustard; vincristine sulfate; zinostatin; and zorubicin hydrochloride.
[00218] Other examples include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; ALL-TK antagonists; angiogenesis inhibitors; antagonist D; antagonist G; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
asulacrine; atamestane; atrimustine; cycloplatam; decitabine; dexamethasone; docetaxel;
docosanol; epirubicin; etoposide phosphategelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; idramantone; ilmofosine; ilomastat; imatinib immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone;
leuprorelin; levamisole; matrilysin inhibitors; matrix metalloproteinase inhibitors; MIF inhibitor; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; human chorionic gonadotrophin; nitric oxide modulators; nitroxide antioxidant; oligonucleotides; onapristone; clitaxel; paclitaxel analogues; nab-paclitaxel; pamidronic acid; proteasome inhibitors; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; tyrosine kinase inhibitors; tyrphostins; or UBC inhibitors. In certain embodiments the secondary active agents include ibrutinib, bendamustine, or rituximab (a CD20 specific chimeric
murine/human monoclonal antibody). [00219] In certain embodiments, the secondary active agent is oblimersen GM-CSF, G-CSF, SCF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.
[00220] In certain embodiments the secondary active agent is a proteasome inhibitor. In one embodiment, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor is bortezomib. In one embodiment, the proteasome inhibitor is carfilzomib. In one embodiment, the proteasome inhibitor is ixazomib.
[00221] In certain embodiments the secondary active agent is an antibody. In one
embodiment, the antibody is riuximab, tositumomab, ibritumomab tiuxetan, campath 1H, HULD10, Appratuzumab, LMB-2, BL22, HuM291, HeFi-1, VH4-34, CTLA4-lg,or anti- CTLA-4.
[00222] In one embodiment, the secondary active agent is ibrutinib, bendamustine, rituximab, or a combination thereof. In one embodiment, the secondary active agent is ibrutinib. In one embodiment, the combination described herein includes a PD-L1 inhibitor (e.g. a PD-L1 antibody) and ibrutinib. In one embodiment, the combination described herein includes durvalumab and ibrutinib, where the combination (and each component thereof) are administered as described herein. In one embodiment, the combination includes administration of durvalumab via IV and ibrutinib via PO. In another embodiment, the secondary active agent is rituximab. In such embodiments, a combination described herein can include a PD-L1 inhibitor (e.g. a PD-L1 antibody), a compound described herein (e.g. lenalidomide or pomalidomide) and rituximab. In one embodiment, the combination described herein includes durvalumab, lenalidomide, and rituximab, where the combination (and each component thereof) are administered as described herein. In one embodiment, the combination described herein includes durvalumab,
pomalidomide, and rituximab, where the combination (and each component thereof) are administered as described herein. In yet another embodiment, the secondary active agent is a combination of rituximab and bendamustine. In such embodiments, a combination described herein can include a PD-L1 inhibitor (e.g. a PD-L1 antibody) and rituximab/bendamustine. In one embodiment, the combination described herein includes durvalumab and rituximab/bendamustine, where the combination (and each component thereof) are administered as described herein.
[00223] In one embodiment, the secondary active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the secondary active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of any optional additional active agents concurrently administered to the patient.
[00224] The secondary active agent can be administered using cyclic therapy as described herein. In one embodiment the secondary active agent is rituximab and can be administered at a concentration of 375 mg/m2. In another embodiment the secondary active agent is rituximab and can be administered at a concentration of 500 mg/m2. In still another embodiment the secondary active agent is rituximab and is administered in accordance with a package insert.
[00225] In one embodiment, rituximab is administered on days 1 and 8 of cycle 1 (e.g., the first cycle). In another embodiment, rituximab is administered on days 1, 8, 15, and 22 of cycle 1 (e.g., the first cycle). In such embodiments, rituximab can be administered at a concentration of 375 mg/ m2. In another embodiment, rituximab is administered at 375 mg/m2 once weekly (e.g., days 2, 8, 15, and 22 of cycle 1) and on day one of each subsequent cycle (e.g., 2-5 cycles). Rituximab can further be administered on day one of every additional cycle in a 28-day cycle at a concentration of 500 mg/ m2. In such embodiments, rituximab can be administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles and optionally between 1-5 total cycles. Secondary active agents described herein can be administered in accordance with established protocols known in the art (e.g., marketed compositions).
[00226] In one embodiment the secondary active agent is bendamustine and can be administered at a concentration of 100 mg/m2. In another embodiment the secondary active agent is bendamustine and can be administered at a concentration of 120 mg/m2. In still another embodiment the secondary active agent is bendamustine and is administered in accordance with a package insert. In one embodiment, bendamustine is administered on days 1 and 2 of cycle 1 (e.g., the first cycle). Bendamustine can further be administered on day one and two of every additional cycle in a 28-day cycle. In such embodiments, bendamustine can be administered over 1, 2, 3, 4, 5, or 6 cycles. In certain instances, the amount of bendamustine administered in a combination described herein is lowered due to toxicity development in the subject. In such occurrences, the amount of bendamustine administered can be reduced to about 50, 60, 70, 80, or 90 mg/m2.
[00227] In another embodiment the combination includes two secondary active agents selected from rituximab and bendamustine where each agent is administered as described above.
[00228] In still another embodiment the secondary active agent is ibrutinib and can be administered at an amount of about 420 mg. In still another embodiment the secondary active agent is ibrutinib and can be administered at an amount of about 560 mg. In still another embodiment the secondary active agent is ibrutinib and is administered in accordance with a package insert. In embodiments, ibrutinib is administered orally once daily.
[00229] In certain embodiments, when the secondary active agent is GM-CSF, G-CSF, SCF or EPO, such secondary active agents are administered subcutaneously during about five days in a four or six week cycle in an amount ranging from about 1 to about 750 mg/m2/day, from about 25 to about 500 mg/m2/day, from about 50 to about 250 mg/m2/day, or from about 50 to about 200 mg/m2/day. In certain embodiments, when the secondary active agent is GM-CSF, it may be administered in an amount of from about 60 to about 500 mcg/m2 intravenously over 2 hours or from about 5 to about 12 mcg/m2/day subcutaneously. In certain embodiments, when the secondary active agent is G-CSF, it may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts. The maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 meg subcutaneously. In certain embodiments, when the secondary active agent is EPO, it may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
5.5. Dosages of Combination Therapies
[00230] In certain embodiments, a therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, or from about 1 to about 100 mg per day. In one embodiment, lenalidomide or pomalidomide is administered in an amount from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day.
[00231] In certain embodiment, a therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, or from about 0.01 to about 250 mg per day. In one embodiment, lenalidomide or pomalidomide is administered in the combinations described herein in an amount from about 1 to about 25 mg per day, from about 2.5 to about 25 mg per day, from about 5 to about 25 mg per day, from about 10 to about 25 mg per day, from about 0.05 to about 10 mg per day, 0.5 to about 10 mg per day, 0.5 to about 5 mg per day, 1 to about 10 mg per day, or about 1 to 5 mg per day.
[00232] In certain embodiments, the therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is about 0.1, about 0.2, about 0.3. about 0.5, about 1, about 2, about 2.5, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. In one embodiment, lenalidomide is administered in an amount of about 1, 2.5, 5, 10, 15, 20, 25, or 50 mg per day. In one embodiment, lenalidomide is
administered in an amount of about , 2.5, 5, 10, 15, 20, or 25 mg per day. In one embodiment, pomalidomide is administered in an amount of about 0.5, 1, 2, 3, 4 or 5 mg per day.
[00233] In one embodiment, the recommended daily dose range of a compound described herein for use in a combination therapy as described herein lie within the range of from about 0.5 mg to about 50 mg per day, preferably given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.01, 0.05,. 0.1, 0.2, 0.3, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.
[00234] In a specific embodiment, the recommended starting dosage of a compound described herein for use in a combination therapy as described herein may be 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In one embodiment, the compound described herein is lenalidomide and has a recommended starting dosage of 1, 2.5, 5, 10, 15, 20, 25, or 50 mg. In one embodiment, the compound is lenalidomide at a starting dosage of 2.5, 5, 10, 25, or 50 mg. In one embodiment, the compound is lenalidomide at a starting dosage of 2.5, 5, 10, or 25 mg. In another embodiment, the recommended starting dosage of a compound described herein for use in a combination therapy as described herein may be 0.5, 1, 2, 3, 4, or 5 mg per day. In one embodiment, the compound described herein is pomalidomide and has a
recommended starting dosage of 0.5, 1, 2, 3, 4, or 5 mg. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, of a compound described herein for use in a combination therapy as described herein can be administered in an amount of about 25 mg/day to patients with NHL (e.g., DLBCL). In a particular embodiment, of a compound described herein for use in a combination therapy as described herein can be administered in an amount of about 10 mg/day to patients with NHL (e.g., DLBCL).
[00235] In certain embodiments, the therapeutically or prophylactically effective amount of a compound described herein for use in a combination therapy as described herein is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 to about 1 mg/kg/day.
[00236] The administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m2/day.
[00237] In certain embodiments, of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 μΜ, about 0.002 to about 200 μΜ, about 0.005 to about 100 μΜ, about 0.01 to about 50 μΜ, from about 1 to about 50 μΜ, about 0.02 to about 25 μΜ, from about 0.05 to about 20 μΜ, from about 0.1 to about 20 μΜ, from about 0.5 to about 20 μΜ, or from about 1 to about 20 μΜ.
[00238] In other embodiments, the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.
[00239] As used herein, the term "plasma concentration at steady state" is the concentration reached after a period of administration of a compound provided herein, e.g., a compound provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.
[00240] In certain embodiments, the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 500 μΜ, about 0.002 to about 200 μΜ, about 0.005 to about 100 μΜ, about 0.01 to about 50 μΜ, from about 1 to about 50 μΜ, about 0.02 to about 25 μΜ, from about 0.05 to about 20 μΜ, from about 0.1 to about 20 μΜ, from about 0.5 to about 20 μΜ, or from about 1 to about 20 μΜ.
[00241] In certain embodiments, the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 μΜ, about 0.002 to about 200 μΜ, about 0.005 to about 100 μΜ, about 0.01 to about 50 μΜ, from about 1 to about 50 μΜ, about 0.01 to about 25 μΜ, from about 0.01 to about 20 μΜ, from about 0.02 to about 20 μΜ, from about 0.02 to about 20 μΜ, or from about 0.01 to about 20 μΜ.
[00242] In certain embodiments, the amount of a compound described herein for use in a combination therapy as described herein administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL. [00243] In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a
combination therapy as described herein at an amount of about 1 mg to about 25 mg per day. In one embodiment, lenalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a combination therapy as described herein at an amount of about 1 mg to about 25 mg per day. In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a combination therapy as described herein at an amount of about 0.5 mg to about 5 mg per day. In one embodiment, pomalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a combination therapy as described herein at an amount of about 0.5 mg to about 5 mg per day. In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a combination therapy as described herein at an amount of about 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per day.
[00244] Checkpoint inhibitors described herein for use in a combination therapy described herein can be administered in amounts from about 0.005 to about 2,000 mg per day, from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day. In one embodiment a checkpoint inhibitor described herein is administered in an amount from about 500 mg to about 2500 mg, 750 mg to about 2250 mg, 1000 mg to about 2000 mg, or about 1200 mg to about 1800 mg.
[00245] Checkpoint inhibitors described herein can be administered in a therapeutically effective amount of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or about 2500 mg. In certain embodiments the checkpoint inhibitor is administered in a therapeutically effective amount of about 1000, 1250, 1500, 1750, or 2000 mg. [00246] In one embodiment the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment the PD-L1 inhibitor is durvalumab. Durvalumab can be administered in an amount from 1 mg to about 2,000 mg per day, from about 100 mg to about 2,000 mg per day, from about 250 mg to about 2,000 mg per day, from about 500 mg to about 2,000 mg per day, 1 mg to about 1,500 mg per day, from about 100 mg to about 1,500 mg per day, from about 250 mg to about 1,500 mg per day, from about 500 mg to about 1,500 mg per day, 1 mg to about 1,000 mg per day, from about 100 mg to about 1,000 mg per day, from about 250 mg to about 1,000 mg per day, from about 500 mg to about 1,000 mg per day, from about 250 mg to about 750 mg per day, or from about 400 mg to about 600 mg per day. In another embodiment the checkpoint inhibitor is durvalumab administered at an amount of about 100, 250, 500, 1,000, 1,500, or 2,000 mg per day. When the CPI is durvalumab it can be administered at a concentration of about 1500 mg. When the CPI is durvalumab it can be administered at a concentration of about 50 mg/mL. In one embodiment, a combination therapy as described herein is co-administered to a patient receiving radiation therapy (e.g., local involved field radiation therapy (IFRT)).
[00247] In certain embodiments, the patient to be treated with a combination therapy described herein has not been treated with anticancer therapy prior to the administration the combination therapy. In certain embodiments, the patient to be treated with a combination therapy described herein has been treated with anticancer therapy prior to administration of a compound described herein for use in a combination therapy described herein. In certain embodiments, the patient to be treated with a combination therapy described herein has developed drug resistance to, or has a cancer that is refractory to, at least one anticancer therapy.
[00248] Checkpoint inhibitors provided herein can be administered according to the routes and dosage amounts generally known to a person of ordinary skill in the art. In certain embodiments, a checkpoint inhibitor described herein is administered in accordance with established protocols known in the art (e.g., marketed compositions). Secondary active agents described herein (e.g. rituximab, ibrutinib, bendamustine) can be administered according to the routes and dosage amounts generally known to a person of ordinary skill in the art. In certain embodiments, a secondary active agent described herein is administered in accordance with established protocols known in the art (e.g., marketed compositions). [00249] Dosages of compounds described herein, checkpoint inhibitors described herein, and secondary active agents described herein can be modified (e.g., increased or decreased dosage) during treatment as set forth herein and understood in the art.
5.6. Cyclic Therapy and Administration
[00250] In one aspect the combination therapies described herein, including components therein (e.g., a compound as described herein and a CPI as described herein or a CPI and one or more secondary active agents) are cyclically administered to a patient. In another aspect the combination therapies described herein are administered cyclically as described herein and a secondary active agent is co-administered in a cyclic administration with such combination therapies. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can be performed independently for each active agent (e.g., a compound described herein, a CPI described herein, and/or a secondary agent described herein) over a prescribed duration of time. In certain embodiments, the cyclic administration of each active agent is dependent upon one or more of the active agents administered to the subject. In one embodiment administration of a compound or checkpoint inhibitor described herein fixes the day(s) or duration of administration of each agent. In another embodiment administration of a compound or checkpoint inhibitor described herein fixes the days(s) or duration of administration of a secondary active agent.
[00251] Thus, in some embodiments a compound described herein, a CPI described herein, and/or a secondary active agent described herein is administered continually (e.g., daily, weekly, monthly) without a rest period. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment or therapeutic agent.
[00252] In one aspect, a compound as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as a component of a combination therapy as described herein once daily for 28 consecutive days in a 28 days cycle. Such combination therapies include administration of a CPI as described herein on one or more days of
administration of the compound (e.g., on day 1 of cycle 1). In another aspect, a compound as described herein is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle. Such a combination therapy includes administration of a CPI as described herein on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The compounds described herein and CPIs described herein of such a combination can be present at a
concentration or amount as set forth herein. In one embodiment the combination therapy includes administration of a compound described herein consecutively for 21 days of a 28 days cycle and administration of a CPI on at least one day of each cycle (e.g., day 1 of cycle 1) in combination with a secondary active agent administered on at least one day of each cycle. In certain embodiments the secondary active agent can be administered once daily, once weekly, or once monthly during the cycling therapy. In another embodiment the secondary active agent is administered once weekly in combination with a combination therapy described herein.
[00253] In one aspect the combination therapy includes lenalidomide as described herein and durvalumab as described herein, where lenalidomide is administered once daily for 21 consecutive days followed by 7 days rest in a 28 days cycle and durvalumab is administered on day one of each 28 days cycle. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (i.e., 12 months). Lenalidomide can be administered at a concentration or amount as described herein. In one embodiment, lenalidomide is administered at an amount of about 5 mg to about 25 mg. Durvalumab can be administered at a concentration described herein. In one embodiment, durvalumab is administered at an amount of about 1,000 mg to about 2,000 mg. In another embodiment, durvalumab is administered at an amount of about 1,500 mg. In another embodiment, the combination therapy includes a secondary active agent as described herein. In one embodiment the secondary active agent is rituximab administered in an amount described herein. In another embodiment, the secondary active agent is ibrutinib administered in an amount described herein. In still another embodiment, the secondary active agent is bendamustine administered in an amount described herein. In yet another embodiment, the secondary agent includes a combination of rituximab and bendamustine each of which are administered in an amount as described herein. Secondary active agents can be administered once or over a predetermined period of time such as, for example, daily, weekly, or monthly. In one embodiment the secondary active agent is administered once daily. In one embodiment the secondary active agent is administered on the first two days of the first cycle and optionally on the first two days of each additional cycle. In one embodiment the secondary active agent is administered once weekly. In one embodiment the secondary active agent is administered once monthly. In another embodiment the secondary active agent is administered about every 7 days for the first cycle and on day 1 of each subsequent cycle. In one embodiment the secondary active agent is rituximab. When the secondary active agent is rituximab, it can be administered intravenously. In one embodiment, the combination is administered according to Table 17.
[00254] In one aspect the combination therapy includes pomalidomide as described herein and durvalumab as described herein, where pomalidomide is administered once daily for 21 consecutive days followed by 7 days rest in a 28 days cycle and durvalumab is administered on day one of each 28 days cycle. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (i.e., 12 months). Pomalidomide can be administered at a concentration or amount as described herein. In one embodiment, pomalidomide is administered at an amount of about 5 mg to about 25 mg. Durvalumab can be administered at a concentration described herein. In one embodiment, durvalumab is administered at an amount of about 1,000 mg to about 2,000 mg. In another embodiment, durvalumab is administered at an amount of about 1,500 mg. In another embodiment, the combination therapy includes a secondary active agent as described herein. In one embodiment the secondary active agent is rituximab administered in an amount described herein. In another embodiment, the secondary active agent is ibrutinib administered in an amount described herein. In still another embodiment, the secondary active agent is bendamustine administered in an amount described herein. In yet another embodiment, the secondary agent includes a combination of rituximab and bendamustine each of which are administered in an amount as described herein. Secondary active agents can be administered once or over a predetermined period of time such as, for example, daily, weekly, or monthly. In one embodiment the secondary active agent is administered once daily. In one embodiment the secondary active agent is administered on the first two days of the first cycle and optionally on the first two days of each additional cycle. In one embodiment the secondary active agent is administered once weekly. In one embodiment the secondary active agent is administered once monthly. In another embodiment the secondary active agent is administered about every 7 days for the first cycle and on day 1 of each subsequent cycle. In one embodiment the secondary active agent is rituximab. When the secondary active agent is rituximab, it can be administered intravenously. [00255] A compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) can independently be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID) as part of a combination therapy described herein. In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term "daily" is intended to mean that a therapeutic agent is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic agent is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term "intermittent" or
"intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound for use in
combination therapies described herein can be administered for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic agent is administered daily or continuously but with a rest period.
[00256] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or
pomalidomide) is administered once a day. In another embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered twice a day. In yet another embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered three times a day. In still another embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered four times a day.
[00257] In certain embodiments, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or
pomalidomide) is administered once per day for one week. In another embodiment, a compound for use in combination therapies described herein is administered once per day for two weeks. In yet another embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered once per day for three weeks. In still another embodiment, a compound for use in combination therapies described herein (e.g. lenalidomide or pomalidomide) is administered once per day for four weeks.
[00258] A checkpoint inhibitor for use in combination therapies described herein can independently be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID) as part of a combination therapy described herein. In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). For example, intermittent administration of a checkpoint inhibitor for use in combination therapies described herein can be administered for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. For example, intermittent administration of a checkpoint inhibitor for use in combination therapies described herein can be administered for once per month, administration in cycles (e.g., monthly administration for two to twelve cycles).
[00259] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, a checkpoint inhibitor for use in combination therapies described herein is administered once a month (e.g. day 1 of each cycle). In another embodiment, a checkpoint inhibitor for use in combination therapies described herein is administered twice a month. In yet another embodiment, a checkpoint inhibitor for use in combination therapies described herein is administered three times a month. In still another embodiment, a checkpoint inhibitor for use in combination therapies described herein is administered four times a month (e.g., weekly). 5.7. Pharmaceutical Compositions
[00260] In one aspect are pharmaceutical compositions and dosage forms, which include a combination therapy as described herein. In another aspect are pharmaceutical compositions and dosage forms that include a combination therapy as described herein and one or more secondary active agents as set forth herein. Such pharmaceutical compositions and dosage forms can include one or more excipients.
[00261] Pharmaceutical compositions, including the individual components of the
combinations described herein, can be supplied as single unit dosage forms. Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or
transcutaneous administration to a patient. In certain embodiments, pharmaceutical
compositions described herein include components supplied as different formulations (e.g. a compound described herein supplied as a oral dosage, a CPI described herein supplied as an IV dosage, and a secondary active agent described herein supplied as an oral dosage or an IV dosage). Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories;
powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
[00262] The composition, shape, and type of dosage forms provided herein may vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
[00263] Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form provided herein depends on a variety of factors, including, but not limited to, the route of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, encompassed herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
[00264] Lactose-free compositions provided herein can comprise excipients that are listed, for example, in the U.S. Pharmacopeia (USP) 25 F20 (2002). In certain embodiments, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In certain embodiments, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
[00265] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations. [00266] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
[00267] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, in certain embodiments, provided herein are anhydrous compositions packaged using materials to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
[00268] Encompassed herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
[00269] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
[00270] In certain embodiments, the dosage forms provided herein include one or more compounds described herein in an amount described herein (e.g., ranging from about 0.10 to about 1000 mg, from about 0.10 to about 500 mg, from about 0.10 to about 200 mg, from about 0.10 to about 150 mg, from about 0.10 to about 100 mg, from about 0.10 to about 50 mg, from about 0.5 to about 10 mg, from about 1 to about 10 mg, from about 1 to about 20 mg, or from about 1 to about 25 mg). In certain embodiments, the dosage forms provided herein include one or more compounds described herein in an amount of about 0.1, about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, about 50, about 100, about 150, or about 200 mg.
[00271] The dosage forms provided herein include a checkpoint inhibitor described herein in an amount described herein (e.g., ranging from about 1 to about 2000 mg, from about 10 to about 2000 mg, from about 1 to about 1500 mg, from about 10 to about 1500 mg, 1 to about 1000 mg, from about 10 to about 1000 mg, from about 500 to about 2000 mg, from about 500 to about 1500 mg, from about 500 to about 1000 mg, from about 1000 to about 2000 mg, or from about 1000 to about 1500 mg. In certain embodiments, the dosage forms provided herein include one or more checkpoint inhibitors described herein in an amount of about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or about 2000 mg.
5.7.1. Oral Dosage Forms
[00272] In certain embodiments, pharmaceutical compositions provided herein that are suitable for oral administration are formulated as discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and may be prepared by some known methods of pharmacy. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
[00273] In certain embodiments, the oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[00274] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by some known methods of pharmacy. In certain embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. [00275] In certain embodiments, a tablet is prepared by compression or molding. In certain embodiments, compressed tablets are be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient. In certain embodiments, molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.
[00276] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
[00277] Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL- PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL RC- 581). Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.
[00278] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
[00279] Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
[00280] Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof. In certain instances
pharmaceutical compositions and dosage forms described herein do not contain croscarmellose sodium.
[00281] Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, MD), a coagulated aerosol of synthetic silica (Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, MA), and mixtures thereof. In certain embodiments, if used at all, lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. In one embodiment pharmaceutical compositions and dosage forms described herein do not include magnesium stearate.
5.7.2. Delayed Release Dosage Forms
[00282] In certain embodiments, the active ingredients provided herein are administered by controlled-release or slow means, or by delivery devices. Examples include, but are not limited to, those described in U.S. Patent Nos. : 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5, 120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety. In certain embodiments, such dosage forms are used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Encompassed herein are single unit dosage forms suitable for oral administration, including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release or slow release.
[00283] All controlled-release or slow release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- release or slow release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
[00284] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
5.7.3. Parenteral Dosage Forms
[00285] Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
[00286] Some suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00287] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms provided herein. For example, cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5, 134,127, the disclosure of which is incorporated herein by reference in its entirety.
5.7.4. Topical and Mucosal Dosage Forms
[00288] Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
[00289] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, in certain embodiments, the excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are nontoxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Additional examples of such ingredients can be found, e.g., in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).
[00290] The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
5.8. Methods of Treating, Preventing, and/or Managing Cancer
[00291] Provided herein are methods of treating, preventing, and/or managing hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein. In one aspect is a method of treating hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein. In another aspect is a method of preventing hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein. In still another aspect is a method of managing hematological cancer or solid tumors by administering to a subject in need thereof a combination therapy described herein. Such combinational therapies include all therapies as provided above (e.g., combination therapies including a compound described herein (e.g. lenalidomide or pomalidomide) together with a CPI described herein and optionally one or more secondary active agents described herein and combination therapies including a CPI described herein together with one or more secondary active agents described herein).
[00292] Patients benefitting from the methods described herein can include patients who have been previously treated for cancer but are non-responsive to standard therapies. In such instances patients may be non-responsive or have developed resistance to anti-cancer treatments. Patients may have cancer refractory or otherwise non-response to at least one anticancer therapy. Patients may also include patients who have not previously been treated by administering a component of a combination therapy as described herein. Patients can also include those patients who have undergone surgery in an attempt to treat the disease or condition at issue. The methods and combination therapies described herein are equally applicable to patients who have not undergone surgery prior to administration. Patients currently taking agents for treating cancer (e.g., concurrently chemotherapy, immunotherapy, biologies, or hormonal therapy), in certain instances, may be excluded from the methods described herein.
[00293] The methods of treating described herein are applicable to all cancer patients regardless of patient's age, although some diseases or disorders are more common in certain age groups. Patients with certain preconditions, having undergone certain medical procedures, or are currently taking certain therapies, in certain instances, may be excluded from the methods described herein.
[00294] Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer.
[00295] Treatment may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including expression levels of checkpoint proteins as identified herein), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from treatment onset until death from any cause. TTP as used herein means the time from treatment onset until tumor progression; TTP does not comprise deaths. As used herein, PFS means the time from treatment onset until tumor progression or death. In the extreme, complete inhibition, is referred to herein as prevention or chemopreventi on .
[00296] In some embodiments of the methods described herein, the treatment can be assessed by one or more clinical endpoints selected from positive tumor response, complete response, partial response or stable disease, increased survival without tumor progression, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor- related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), or increased Overall Survival (OS).
[00297] Thus, provided herein are methods for achieving one or more clinical endpoints associated with treating a hematological cancer (or solid tumor) described herein. In one embodiment, a patient described herein can show a positive tumor response, such as inhibition of tumor growth or a reduction in tumor size after treatment with a combination described herein. In certain embodiments, a patient described herein can achieve a Response Evaluation Criteria in Solid Tumors (for example, RECIST 1.1) of complete response, partial response or stable disease after administration of an effective amount a combination described. In certain embodiments, a patient described herein can show increased survival without tumor progression. In some embodiments, a patient described herein can show inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including tumor secreted hormones, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and/or increased Overall Survival (OS), among others.
[00298] In another embodiment, methods are provided for increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein. In one embodiment, a method is provided for increasing the overall survival of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein. In one embodiment, is a method for increasing the objective response rate of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein. In one embodiment, is a method for increasing the time to progression of a patient having a hematological cancer described herein comprising
administering an effective amount of a combination as described herein. In one embodiment, is a method for increasing the progression-free survival of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein as described herein. In one embodiment, is a method for increasing the time-to-treatment failure of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein. In all such embodiments, the combination can be administered so that it includes lenalidomide or pomalidomide in combination with a CPI as described herein.
[00299] Further provided herein are methods for decreasing mortality of a patient having a hematological cancer described herein comprising administering an effective amount of a combination as described herein.
[00300] The methods described herein are methods useful for treating, preventing, and/or managing cancer of the skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. In one embodiment, cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, follicular lymphoma, low grade follicular lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma.
[00301] In another aspect is a method of treating, preventing, and/or managing hematological cancer by administering to a subject in need thereof a combination therapy as described herein. In certain embodiments the hematological cancer is myeloma, lymphoma or leukemia. In another aspect is a method of treating hematological cancer by administering to a subject in need thereof a combination therapy as described herein. In certain embodiments the hematological cancer is myeloma, lymphoma or leukemia. In certain embodiments, the cancer is myeloma. In certain embodiments, the cancer is lymphoma. In another embodiment the hematological cancer is lymphoma or chronic lymphocytic leukemia (CLL). In one embodiment the hematological cancer is Hodgkin lymphoma (HL) or CLL. In one embodiment the hematological cancer is CLL. In one embodiment the hematological cancer is HL. In one embodiment the hematological cancer is non-Hodgkin's lymphoma (NHL). In certain embodiments the hematological cancer includes indolent lymphomas including for example DLBCL, follicular lymphoma, or marginal zone lymphoma. In another embodiment the hematological cancer is a cancer set forth in Table 1. In certain embodiments, the hematological cancer is drug resistant to at least one anticancer therapy. In certain embodiments the hematological cancer is refractory to at least one anticancer therapy. In certain embodiments, the hematological cancer is metastatic. In another embodiment, are methods for increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having myeloma, leukemia, or lymphoma as described herein comprising administering an effective amount of a combination as described herein.
[00302] In another aspect is a method for treating a B-cell malignancy comprising
administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[00303] In one embodiment, the B-cell malignancy is selected from the group consisting of mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B- cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), and modular lymphocyte pre-dominant Hodgkin lymphoma. In another embodiment, are methods for increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), or modular lymphocyte pre-dominant Hodgkin lymphoma comprising administering an effective amount of a combination as described herein.
[00304] Table 1 : Exemplary B-cell Non-Hodgkin Lymphoma Histologies (Based on the 2008 WHO Lymphoma Classification) for Phase 1 Dose Finding Cohorts
Figure imgf000065_0001
Abbreviations: ALK = Anaplastic Lymphoma Kinase; WHO = World Health Organization^ Transformed lymphoma will be included (but is not part of the WHO 2008 Classification).
Richter's transformation will be included (but is not part of the WHO 2008 Classification).
[00305] In one aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). [00306] In another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no
administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary active agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). In one embodiment, the secondary active agent is rituximab.
[00307] In still another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00308] In still another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00309] In still another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00310] In still another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00311] In one embodiment, the combination for treating a B-cell malignancy described herein includes lenalidomide, a PD-L1 inhibitor, and a proteasome inhibitor. The combination can further include dexamethasone. In one embodiment, the combination includes lenalidomide, dexamethasone, and durvalumab. In one embodiment, the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
[00312] In one embodiment the method is a method of treating or managing non-Hodgkin's lymphoma by administering a combination therapy described herein to a subject in need thereof. In some embodiments, provided herein are methods for the treatment or management of diffuse large B-cell lymphoma (DLBCL) by administering a combination therapy as described herein to a subject in need thereof. In another embodiment is a method for treating, preventing, and/or managing R/R (relapsed/refractory) lymphoma by administering a combination therapy as described herein. In yet another embodiment is a method for treating, preventing, and/or managing follicular lymphoma (FL) by administering a combination therapy as described herein.
[00313] In one aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is
administered for 1 to 13 cycles of 28 days (e.g., about 12 months). [00314] In another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary active agent is administered weekly. In one embodiment, the combination therapy is
administered for 1 to 13 cycles of 28 days (e.g., about 12 months). In one embodiment, the secondary active agent is rituximab.
[00315] In still another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00316] In still another aspect is a method of treating NHL by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00317] In still another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). [00318] In still another aspect is a method of treating NHL by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00319] In another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00320] In still another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating NHL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00321] In another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00322] In still another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating a B-cell malignancy by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00323] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having NHL.
[00324] In another aspect is a method of treating diffuse large B-cell lymphoma (DLBCL) by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00325] In another aspect is a method of treating DLBCL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00326] In still another aspect is a method of treating DLBCL by administering a
combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). [00327] In still another aspect is a method of treating DLBCL by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00328] In still another aspect is a method of treating DLBCL by administering a
combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00329] In still another aspect is a method of treating DLBCL by administering a
combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00330] In another aspect is a method of treating DLBCL by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine. [00331] In still another aspect is a method of treating DLBCL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating DLBCL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00332] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having DLBCL.
[00333] In yet another aspect is a method of treating follicular lymphoma (FL) by
administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00334] In another aspect is a method of treating FL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00335] In still another aspect is a method of treating follicular lymphoma (FL) by
administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). In still another aspect is a method of treating FL by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00336] In still another aspect is a method of treating follicular lymphoma (FL) by
administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). In still another aspect is a method of treating FL by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00337] In another aspect is a method of treating FL by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine. [00338] In still another aspect is a method of treating FL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating FL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00339] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having FL.
[00340] In yet another aspect is a method of treating marginal zone lymphoma (MZL) by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00341] In another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00342] In still another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). In still another aspect is a method of treating MZL by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00343] In still another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). In still another aspect is a method of treating MZL by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00344] In another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00345] In still another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating MZL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00346] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having MZL.
[00347] In another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00348] In one embodiment, the multiple myeloma is relapsed multiple myeloma. In one embodiment, the multiple myeloma is refractory multiple myeloma. In one embodiment, the multiple myeloma is relapsed/refractory (R/R) multiple myeloma. In one embodiment, the patient having R/R multiple myeloma has impaired renal function. In one embodiment, the multiple myeloma is newly diagnosed multiple myeloma. In one embodiment, the multiple myeloma is smoldering multiple myeloma.
[00349] In another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00350] In still another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00351] In still another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00352] In still another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00353] In still another aspect is a method of treating multiple myeloma (e.g., relapsed multiple myeloma, refractory multiple myeloma, R/R multiple myeloma, and newly diagnosed multiple myeloma) by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00354] In a specific embodiment, the second active agent is lenalidomide. In another embodiment, the second active agent is pomalidomide.
[00355] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having multiple myeloma.
[00356] In another aspect is a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00357] In still another aspect is a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00358] In another aspect is a method of treating chronic lymphocytic leukemia (CLL) by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00359] In another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00360] In still another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00361] In still another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00362] In still another aspect is a method of treating CLL by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00363] In still another aspect is a method of treating CLL by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly).
[00364] In a specific embodiment, the second active agent is lenalidomide. In another embodiment, the second active agent is pomalidomide.
[00365] In another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00366] In still another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating CLL by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00367] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having CLL. [00368] In another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the
compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00369] In another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no
administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months).
[00370] In still another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1).
[00371] In still another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). [00372] In another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00373] In still another aspect is a method of treating carcinoma or sarcoma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating multiple myeloma by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00374] The carcinoma is a carcinoma as described herein and in certain embodiments is primary ductal carcinoma, lung carcinoma, colon adenocarcinoma, histiocytic lymphoma, colorectal carcinoma, hepatocellular carcinoma, or colorectal adenocarcinoma. In another embodiment the method is a method of treating, preventing, and/or managing a sarcoma described herein.
[00375] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having carcinoma or sarcoma.
[00376] In another aspect is a method for treating myelodysplastic syndromes (MDS) by administering to a subject in need thereof a combination therapy as described herein. The MDS can be a low risk MDS (LR MDS). The MDS can be a high risk MDS (HR MDS). In one embodiment the MDS develops into acute myelogenous leukemia (AML). In another embodiment the MDS develops into chronic myelogenous leukemia (CML). In yet another embodiment the MDS develops into acute lymphocytic leukemia (ALL). In still another embodiment the MDS develops into chronic lymphocytic leukemia (CLL). In certain instances the MDS is resistant to treatment with hypomethylating agents (HMAs). In one embodiment the MDS is developed from a treatment with a therapy (tMDS), e.g., therapy induced.
[00377] In another aspect is a method of treating myelodysplastic syndromes by administering a combination therapy described herein where the combination therapy includes a CPI described herein and one or more secondary active agents. The CPI can be administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The one or more secondary active agents can be administered as described herein, for example, for rituximab, ibrutinib, and bendamustine.
[00378] In still another aspect is a method of treating myelodysplastic syndromes by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab administered as described herein. In yet another aspect is a method of treating myelodysplastic syndromes by administering a combination therapy described herein where the combination therapy includes durvalumab administered as described herein in combination with rituximab and bendamustine, both of which are administered as described herein.
[00379] In one embodiment, the combination for treating MDS includes lenalidomide, a PD- Ll inhibitor, and a proteasome inhibitor. The combination can further include dexamethasone. In one embodiment, the combination includes lenalidomide, dexamethasone, and durvalumab. In one embodiment, the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having MDS.
[00380] Accordingly, provided herein is a method of treating AML in a subject in need thereof by administering a combination therapy as described herein. The AML can be R/R AML, trilineage dysplasia AML (AML-TLD), or therapy induced AML (tAML). The patient is as described herein and in certain instances has undergone treatment with a HMA. In one embodiment, the patient has HMA refractory AML. [00381] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having AML.
[00382] Also provided herein are methods of treating ALL in a subject in need thereof by administering a combination therapy described herein. In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having ALL.
[00383] Also provided herein is a method of treating CML in a subject in need thereof by administering a combination therapy as described herein. The CML can be R/R CML. In one embodiment a combination therapy described herein is co-administered according to the methods and description herein with a secondary active agent. The secondary active agent can be an anticancer agent as described herein. In one embodiment the secondary active agent is a tyrosine kinase inhibitor (TKI). In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having CML.
[00384] Further provided herein are methods for treating myelofibrosis using a combination therapy described herein.
[00385] In certain embodiments administration of a combination therapy as described herein modulates expression levels of at least one CPI described herein (e.g., PD-L1). Thus, provided herein are methods of determining the expression of at least one CPI, where the determination of the expression level is performed before, during, and/or after administration of a combination therapy described herein. The CPI expression levels determined before, during, and/or after administration of a combination therapy as described herein can be compared against each other or standard controls. Such comparisons can translate into determination of the efficacy of the administered treatment where in one embodiment a level of decreased expression of a given CPI indicates a greater effectiveness of the combination therapy.
[00386] In certain instances the combination therapies described herein reduce or eliminate minimal residual disease (MRD) state of a MDS described herein. Accordingly, in one embodiment a combination therapy described herein is administered to a patient in need thereof, wherein said administration reduces or eliminates MRD. In one embodiment, the combination therapy is administered after administration of chemotherapy. In another embodiment, the combination therapy is administered during chemotherapy. In yet another embodiment, the combination therapy is administered as a chemotherapeutic therapy.
[00387] Also provided herein are methods where a combination therapy described herein is administered before or after a stem cell transplant (SCT) such as a bone marrow stem cell transplant (BMSCT). In certain instances the level of expression of a CPI is determined for such stem cells pre- and post- transplant and pre- and post- administration with a combination therapy as described herein. In one embodiment, a combination therapy described herein is administered after a SCT (e.g., 1-24 hours, 1-3 days, 1-10 days, 1-3 months, 3-6 months, or 6-12 months post transplant). In another embodiment, a combination therapy described herein is administered within 180 days of a SCT. In certain embodiments administration of a combination therapy described herein reduces or eliminates development of graft v. host disease in a patient. In another embodiment administration of a combination therapy as described herein reduces or eliminates the need for immunosuppressive therapies following a SCT. In one embodiment, the stem cell transplant is a hematopoietic stem cell transplant. In one embodiment, the transplant is a peripheral blood transplant. In some embodiments, the stem cell transplant is an autologous stem cell transplant.
[00388] In another aspect administration of a combination therapy described herein is performed after a donor lymphocyte infusion (DLI). DLI can be used to stimulate a donor- versus-leukemia (GVL) reaction and thus eradicate the malignant clone of cells. DLI uses the collection (from the original donor) of peripheral lymphocytes during an apheresis procedure; donors generally undergo 2 to 8 procedures. The lymphocytes are then infused into the patient either immediately or after frozen storage. Donor lymphocyte infusion differs from allogeneic bone marrow transplantation in that it is not preceded by chemotherapy and T cells are not depleted. Lymphocyte infusion with a defined T-cell dose can cause a profound GVL effect and can be an effective form of salvage immunotherapy in allogeneic marrow transplanted recipients. In certain embodiments DLI lowers treatment-related morbidity and mortality when compared to second allogeneic transplantation.
[00389] In another aspect administration of a combination therapy described herein prolongs complete remission (CR) of the MDS after chemotherapy. CR can be prolonged by administering the combination therapies described herein (and optionally with co-administration of secondary active agents described herein) for MDS including when MDS develops into AML, ALL, CML, and CLL as described herein. In another aspect administration of a combination therapy described herein prolongs complete remission (CR) of the cancer (e.g. solid tumor or
hematological cancer) after chemotherapy.
[00390] In certain instances treatment using the combination therapies described herein can be monitored or determined using assays to determine expression levels of checkpoint proteins described herein (e.g., PD-L1, ΤΊΜ-3, LAG-3, CTLA-4, OX40, Treg, CD25, CD127, FoxP3). Determining the expression of such checkpoint proteins can be performed before, during, or after completion of treatment with a combination therapy described herein. Expression can be determined using techniques known in the art, including for example flow-cytometry.
[00391] In certain embodiments, the MDS is drug resistant to at least one anticancer therapy. In certain embodiments the MDS is refractory to at least one anticancer therapy.
[00392] In one aspect is a method of treating MDS by administering a combination therapy described herein where the combination therapy includes a compound described herein and one CPI described herein where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; and the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1). In one embodiment, the combination therapy is
administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The MDS can develop into AML, CML, ALL, or CLL as described herein.
[00393] In another aspect is a method of treating MDS by administering a combination therapy described herein where the combination therapy includes a compound described herein, one CPI described herein, and a secondary active agent, where the compound is administered once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle; the CPI is administered on one or more days of administration of the compound (e.g., on day 1 of cycle 1), and the secondary agent is administered weekly. In one embodiment, the combination therapy is administered for 1 to 13 cycles of 28 days (e.g., about 12 months). The MDS can develop into AML, CML, ALL, or CLL as described herein. [00394] In still another aspect is a method of treating MDS by administering a combination therapy described herein where the combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). The MDS can develop into AML, CML, ALL, or CLL as described herein.
[00395] In still another aspect is a method of treating MDS by administering a combination therapy described herein combination therapy includes: lenalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly). The MDS can develop into AML, CML, ALL, or CLL as described herein.
[00396] In still another aspect is a method of treating MDS by administering a combination therapy described herein where the combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); and durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1). The MDS can develop into AML, CML, ALL, or CLL as described herein.
[00397] In still another aspect is a method of treating MDS by administering a combination therapy described herein combination therapy includes: pomalidomide administered at an amount and frequency as described herein (e.g., once daily for 21 consecutive days followed by 7 days of rest (e.g., no administration of the compound/discontinuation of treatment) in a 28 days cycle); durvalumab administered at an amount and frequency as described herein (e.g., monthly in a 28 day cycle) one or more days of administration of the compound (e.g., on day 1 of cycle 1) and rituximab administered in an amount and frequency as described herein (e.g. weekly). The MDS can develop into AML, CML, ALL, or CLL as described herein. [00398] In certain embodiments, a combination therapy as described herein is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acute myelogenous leukemia.
[00399] In certain embodiments, a combination therapy as described herein is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
[00400] Further provided herein are methods of treating solid tumors by administering a combination therapy described herein to a subject in need thereof. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant to at least one anticancer therapy. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma.
[00401] In one embodiment, provided herein are methods of preventing relapsed/refractory multiple myeloma in patients by administering an effective amount of a combination therapy as described herein. The patient may also have impaired renal function or a symptom thereof.
[00402] In certain embodiments, provided herein are methods for treating, preventing, and/or managing relapsed/refractory multiple myeloma in patients with impaired renal function by administering a combination therapy as described herein.
[00403] In another aspect is a method of treating hepatocellular carcinoma (HCC) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[00404] As discussed elsewhere herein, encompassed herein is a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. A combination therapy as described herein can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with
conventional therapy.
[00405] In another embodiment, encompassed herein is a method of treating, preventing and/or managing cancer, which comprises administering a combination therapy described herein in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. The combined use of the combination therapy described herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that the combination therapies described herein may provide additive or synergistic effects when given concurrently with conventional therapy. In certain embodiments provided herein is a combination therapy as described herein for use in a method of treating, preventing and/or managing cancer, wherein the method comprises the above defined administration step.
[00406] In a specific embodiment, the cancer is glioblastoma, primary ductal carcinoma, leukemia, acute T cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid lymphoma (CML), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), lung carcinoma, colon adenocarcinoma, histiocytic lymphoma, colorectal carcinoma, colorectal adenocarcinoma, prostate cancer, non-Hodgkin lymphoma (e.g., DLBCL, MZL, or FL), multiple myeloma, or retinoblastoma.
[00407] In another aspect is a method for treating a T-cell malignancy comprising
administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein.
[00408] In one embodiment, the T-cell malignancy is selected from the group consisting of peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis, angioimunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, lymphoblastic lymphoma, treatment related T-cell lymphoma; T-cell NHL, and chronic T-cell lymphoma. In one embodiment, the method includes a combination described herein where the combination includes an immunomodulatory compound selected from lenalidomide or pomalidomide.
[00409] In one embodiment, the T-cell malignancy is peripheral T-cell lymphoma (not otherwise specified). In one embodiment, the T-cell malignancy is analplastic large cell lymphoma. In one embodiment, the T-cell malignancy is Sezary syndrome, primary cutaneous anaplastic large cell lymphoma or lymphomatoid papulosis. In one embodiment, the T-cell malignancy is angioimunoblastic lymphoma. In one embodiment, the T-cell malignancy is cutaneous T-cell lymphoma. In one embodiment, the T-cell malignancy is adult T-cell leukemia/lymphoma (ATLL). In one embodiment, the T-cell malignancy is blastic K-cell lymphoma. In one embodiment, the T-cell malignancy is lymphoblastic lymphoma. In one embodiment, the T-cell malignancy is treatment related T-cell lymphoma. In one embodiment, the T-cell malignancy is T-cell NHL. In one embodiment, the T-cell malignancy is chronic T- cell lymphoma.
[00410] In one embodiment, the combination for treating a T-cell malignancy described herein includes lenalidomide, a PD-Ll inhibitor, and a proteasome inhibitor. The combination can further include dexamethasone. In one embodiment, the combination includes lenalidomide, dexamethasone, and durvalumab. In one embodiment, the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
[00411] In one embodiment, the method includes increasing the overall survival, objective response rate, time to progression, progression-free survival and/or time-to-treatment failure of a patient having peripheral T-cell lymphoma (not otherwise specified), analplastic large cell lymphoma, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma and
lymphomatoid papulosis, angioimunoblastic lymphoma, cutaneous T-cell lymphoma, adult T- cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, lymphoblastic lymphoma, treatment related T-cell lymphoma; T-cell NHL, or chronic T-cell lymphoma.
[00412] In certain embodiments, a combination therapy as described herein is administered with melphalan and dexamethasone to patients with amyloidosis. In certain embodiments, a combination therapy described herein and steroids can be administered to patients with amyloidosis.
[00413] In certain embodiments, a combination therapy as described herein is administered with rituximab for treating non-Hodgkin lymphoma (NHL).
[00414] In certain embodiments, a combination therapy as described herein is administered with ibrutinib for treating non-Hodgkin lymphoma (NHL).
[00415] In certain embodiments, a combination therapy as described herein is administered with bendamustine for treating non-Hodgkin lymphoma (NHL). [00416] In certain embodiments, a combination therapy as described herein is administered with rituximab/bendamustine for treating non-Hodgkin lymphoma (NHL).
[00417] In another aspect is a method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
[00418] In another aspect is a method for treating lymphoma as described herein comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
[00419] In another aspect is a method for treating mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, marginal-zone lymphoma (MZL) including splenic variants, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), classical type Hodgkin lymphoma (HL), or modular lymphocyte pre-dominant Hodgkin lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy as described herein in combination with rituximab, ibrutinib, or bendamustine/rituximab.
[00420] In certain embodiments, a combination therapy as described herein is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
[00421] In certain embodiments, a combination therapy as described herein is administered in combination with a secondary active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapsed brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent malignant gliomas; temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma. [00422] In certain embodiments, a combination therapy as described herein is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, or PLX3397
(Plexxikon), or a combination thereof, to patients with metastatic breast cancer.
[00423] In certain embodiments, a combination therapy as described herein is administered with temozolomide to patients with neuroendocrine tumors.
[00424] In certain embodiments, a combination therapy as described herein is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.
[00425] In certain embodiments, a combination therapy as described herein is administered with gemcitabine to patients with pancreatic cancer.
[00426] In certain embodiments, a combination therapy as described herein is administered with capecitabine and/or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
[00427] In certain embodiments, a combination therapy as described herein is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
[00428] In certain embodiments, a combination therapy as described herein is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT- 11.
[00429] In certain embodiments, a combination therapy as described herein is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.
[00430] In certain embodiments, a combination therapy as described herein is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
[00431] In certain embodiments, a combination therapy as described herein is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma. [00432] In certain embodiments, a combination therapy as described herein is administered in combination with gemcitabine, erlotinib, geftinib, and/or irinotecan to patients with non-small cell lung cancer.
[00433] In certain embodiments, a combination therapy as described herein is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.
[00434] In certain embodiments, a combination therapy as described herein is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy.
[00435] In certain embodiments, a combination therapy as described herein is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer.
[00436] In certain embodiments, a combination therapy as described herein is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.
[00437] In certain embodiments, a combination therapy as described herein is administered in combination with oblimersen to patients with small cell lung cancer.
[00438] In certain embodiments, a combination therapy as described herein is administered in combination with ABT-737 (Abbott Laboratories) and/or obatoclax (GXl 5-070) to patients with lymphoma and other blood cancers.
[00439] In certain embodiments, a combination therapy as described herein is administered alone or in combination with a secondary active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
[00440] In certain embodiments, a combination therapy as described herein is administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) or dacarbazine, or a combination thereof, to patients with various types or stages of melanoma.
[00441] In certain embodiments, a combination therapy as described herein is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.
[00442] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.
[00443] In certain embodiments, a combination therapy as described herein is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin, vincristine and/or dexamethasone. In one embodiment, a combination therapy as described herein is administered to patients with relapsed or refractory multiple myeloma in combination with dexamethasone. In one embodiment, a combination therapy as described herein is administered to patients with multiple myeloma in combination with dexamethasone. In one embodiment, the combination includes lenalidomide, a PD-L1 inhibitor, and a proteasome inhibitor. The combination can further include dexamethasone. In one embodiment, the combination includes lenalidomide, dexamethasone, and durvalumab. In one embodiment, the combination includes lenalidomide dexamethasone durvalumab, and bortezomib, carfilzomib, or ixazomib.
[00444] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
[00445] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM- CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon, or a combination thereof. [00446] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
[00447] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.
[00448] In certain embodiments, a combination therapy as described herein is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
[00449] In certain embodiments, a combination therapy as described herein is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
[00450] Also encompassed herein is a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to the patient (e.g., a human) combination therapy as described herein. Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof. The administration of a combination therapy as described herein, in certain embodiments, alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti-cancer drug.
[00451] In one embodiment, a compound provided herein as administered in a combination therapy as described herein is administered orally and daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In certain embodiments, a compound provided herein as administered in a combination therapy as described herein is administered in combination with specific agents such as heparin, aspirin, Coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
[00452] In one embodiment, a compound provided herein as administered in a combination therapy as described herein is administered to patients with diseases and disorders associated with or characterized by, undesired angiogenesis in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.
[00453] The methods of treating, preventing, and/or managing described hereinabove can include combination therapies described herein that are administered using cycling therapy as described herein.
[00454] It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also included within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.
6 EXAMPLES
[00455] Example 1 :
[00456] Here is described a Phase 1/2 open label multicenter study to assess efficacy, safety, and tolerability of combination therapies including an Immunomodulatory agent and a checkpoint inhibitor in subjects with relapsed/refractory lymphoma or MDS is performed.
[00457] The study will examine efficacy of combination therapies using an
Immunomodulatory agent and a checkpoint inhibitor for indications described herein. The study will be conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practices (GCPs).
[00458] This is a multicenter, open label, Phase 1/2 study assessing the safety, tolerability, PK, Pd, and preliminary efficacy of durvalumab as given in combination with
Immunomodulatory agents in select subtypes of MDS including AML, CML, ALL, and CLL. The current study will include testing of combinational therapies in combination with other anticancer agents, including for example rituximab. [00459] Rationale: Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types of cancers. Most tumors show infiltration by TILs, but tumors modulate the local microenvironment through expression of inhibitory molecules. Without being bound by any particular theory, engagement of TIL cell-surface receptors with these inhibitory ligands likely leads to a dysfunctional immune response, causes T-cell exhaustion, and likely facilitates tumor progression. It is increasingly appreciated that cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors. Novel monoclonal antibodies (mAbs) that block these inhibitory receptors have shown significant clinical activity across a number of tumor types.
[00460] Blockade of immune-checkpoint inhibitors such as cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), PD-1, and PD-L1 have shown clinical activity not only in conventionally immune-responsive tumors such as melanoma and renal cell carcinoma but also in non-small cell lung cancer and prostate cancer. Pembrolizumab and nivolumab are both PD-1 blocking antibodies and the first in the anti-PD-1 pathway family of checkpoint inhibitors to gain approval from the US Food and Drug Administration (FDA), pembrolizumab for melanoma and nivolumab for melanoma and squamous non-small cell lung cancer. Both pembrolizumab and nivolumab have received European Commission regulatory approval for the treatment of metastatic melanoma. The European Commission has also approved nivolumab for the treatment of advanced previously treated squamous NSCLC. Nivolumab has gained approval for the treatment of melanoma in Japan.
[00461] Lymphomas and leukemias comprise multiple histologies. It is hypothesized without being bound by any particular theory that checkpoint inhibitors such as durvalumab have activity in multiple indications based on known expression pattern of PD-Ll/PD-1, available preclinical data, and recent clinical data utilizing nivolumab or pembrolizumab in relapsed refractory classical Hodgkin lymphoma and promising early data of pidilizumab alone or in combination with rituximab in diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL), respectively; also nivolumab monotherapy has shown antitumor activity in DLBCL, FL and T- cell lymphomas.
[00462] The programmed cell death- 1 (PD-1) plays an important role in the regulation of the immune response. The PD-1 receptor, in conjunction with receptor ligands PD-L1 and PD-L2, functions to regulate the immune system primarily by down regulating signals of the T-cell receptor. PD-Ll expressed on tumor cells binds to PD-1 on T-cells which leads to down- regulation of T-cell activity and allows tumor cells to evade the immune response.
[00463] Based on in vitro studies, an antibody that blocks the interaction between PD-Ll and its receptors can relieve PD-Ll -dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T-cells. The levels of tumor-infiltrating lymphocytes, and more specifically cytotoxic T-cells, have been correlated with improved prognosis in a number of cancers including colorectal, melanoma, and lung. Based on these findings, an anti -PD-Ll antibody could be used therapeutically to enhance antitumor immune responses in multiple forms of cancer. Lenalidomide and pomalidomide has pleiotropic activities including a capacity to activate K cells, to increase T-cell proliferation and function, and to enhance macrophage- mediated ADCC of rituximab-coated tumor cells. The main molecular target of lenalidomide is the E3 ubiquitin ligase cereblon that was recently shown to trigger induction of cytokine production by T-cells. Follicular lymphoma infiltrating CD4+ and CD8+ tumor induced immunosuppression in the context of increased expression of B7- related inhibitory ligands (including PD-Ll) down-regulates activated Rho-GTPases RhoA, Racl, and Cdc42, key regulators of T-cell synapse actin dynamics. T-cells display immunological synapse dysfunction with impaired F-actin polymerization and reduced effector function. Without being bound by any particular theory, lenalidomide can repair the Rho A mediated T-cell synapse defect present in cancer patients thereby restoring T-cell functions and potentially enabling the effect of immunotherapies, lenalidomide and rituximab in relapsed, refractory and first line FL, based on Phase 2 results suggesting that this combination may be a reasonable alternative to traditional chemoimmunotherapy .
[00464] Preclinical studies with respect to multiple myeloma have demonstrated that lenalidomide enhances immune checkpoint blockade (i.e., anti- PD-1/PD-L1) induced immune response in patient-derived primary myeloma cells. Other studies demonstrate that lenalidomide reduced PD-Ll expression on myeloma cells, and that lenalidomide exposure resulted in a decrease in the expression of PD-1 on T-cells and induced amplified responses to myeloma vaccine. [00465] Treatment Period: Subjects begin treatment following confirmation of eligibility. For all subsequent visits, an administrative window of ± 2 days for study Day 1 visits and ± 1 for scheduled interim study visits (e.g., Day 18, 15, 22 visits) are allowed. Subjects who receive lenalidomide should have at least a 7-day rest between two 21 -day treatment periods and therefore this should be taken into consideration when applying the visit window of ± 2 days. If assessments are performed within 48 hours of Day 1 of each cycle, safety laboratory and physical examinations need not be repeated on Day 1. Treatment cycles are 28 days in duration. Efficacy Assessments. For lymphoma, disease response to treatment is determined by the Lugano Classification including a careful review of imaging and laboratory studies and clinical findings. Integrated PET-CT is preferred for response assessment of FDG-avid lymphomas (e.g., DLBCL, HL, FL, transformed large cell lymphoma), while dedicated CT scan alone is preferred for FDG non-avid and variably FDG-avid histologies (e.g., CLL/SLL, MZL).
[00466] Minimal Residual Disease (Immunophenotyping of Blood for Circulating CLL Cells by Multiparameter Flow Cytometry) (CLL) If CBC with differential demonstrates the normalization of WBC to normal limits and no evidence of lymphocytosis, peripheral blood sample will be obtained (within 14 days) to determine the MRD status of the CLL in peripheral blood by multiparameter flow cytometry. In one section of the study, subjects receive:
• Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13 (i.e., 12 months);
• Lenalidomide (PO) once daily on Days 1 to 21 (inclusive) of: Cycles 1 through 13 in indolent NHL (i.e., FL or MZL) or Until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL (e.g., DLBCL); and
• Rituximab (IV) infusion on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 from Cycles 2 through 5.
[00467] All treatment cycles are 28 days. Durvalumab infusion is administered before any other IP on the days which more than one investigational treatment should be given (e.g., Day 1 of Cycles 1 through 13), and then lenalidomide administration and rituximab infusion are recommended to follow, respectively.
[00468] Initial cohorts of 3 subjects are treated at varying dose levels. If one DLT occurs in the first 3-subject cohort at a dose level during the DLT observation period (i.e., from the time of the first IP dose through completion of Cycle 2), that cohort enrolls up to 6 subjects. Even in the absence of a DLT, additional subjects may be evaluated within a dose cohort if recommended by the SRC to adequately evaluate the safety or treatment effects of durvalumab in combination with lenalidomide and/or rituximab (depending on dose level). If dose level 1 is found to be the NTD, the next dose level may be explored.
[00469] Table 17: Dose Finding: Arm A Dose Levels
Figure imgf000100_0001
[00470] Efficacy Analysis: In the dose confirmation part and dose expansion part, treatment efficacy is evaluated by different histology cohorts for each treatment arm. Efficacy analysis is performed for particular treatment arm and subject histology cohort by combining data from both dose confirmation part and dose expansion part. Efficacy analysis is also performed separately for dose confirmation part and dose expansion part as well.
[00471] For lymphoma subjects, response evaluation is based on TvVG Response Criteria for Malignant Lymphoma (the Lugano Classification). The overall response rate (ORR) is defined as the percent of subjects with best response of CR or PR. Duration of response (DoR) is defined for responders only as the time from the first response (CR or PR) to For CLL subjects, response evaluation will be based on TvVCLL guidelines for diagnosis and treatment of CLL. The overall response rate (ORR) is defined as the percent of subjects with best response of CR, CRi, nPR, PR, or PRL. Duration of response (DoR) is defined for responders only as the time from the first response (CR, CRi, nPR, PR, or PRL) to disease progression or death. Overall survival is defined as the time from randomization until death from any cause. Complete response (CR) is defined as absence of all detectable cancer after treatment. Pathological complete response (pCR) is deinfed as no evidence of cancer found in a tissue sample. Partial response (PR) is defined as reduction of cancer by 30% or more.
[00472] The response rate based on the best response during durvalumab treatment as well as during entire efficacy evaluation period is summarized by subject histology cohort for each treatment arm.
[00473] For subjects with response, duration of response is censored at the last date that the subject was known to be progression free. Duration of response is analyzed using the Kaplan- Meier method. Median duration of response along with two-sided confidence interval is provided for each treatment arm and subject histology cohort.
[00474] Progression-free survival (PFS) is calculated as the time from first IP dose to the first documented progression or death due to any cause during the entire efficacy evaluation period. Median PFS including 2-sided 95% CL is provided for each histology cohort within the same treatment arm.
[00475] Safety Analysis: Safety analysis includes all subjects in the safety population.
Investigational product exposure is summarized for each treatment arm and histology cohort including duration of investigational product, total dose taken, and dose reductions. Adverse events, vital sign measurements, clinical laboratory measurements, physical examination and concomitant medications is summarized by treatment arm and histology cohort.
[00476] All of the references cited herein are incorporated by reference in their entirety. While the methods provided herein have been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and
modifications can be made without departing from the spirit and scope as recited by the appended claims.
[00477] The embodiments described above are intended to be merely exemplary and those skilled in the art will recognize or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures.
[00478] Example 2. [00479] This example describes a Phase 1/2, open label, multicenter study is used to assess the safety and tolerability of durvalumab (anti-PD-Ll antibody) administered as a monotherapy and durvalumab administered in combination with lenalidomide, ibrutinib, rituximab, and
bendamustine in subjects with lymphoma or chronic lymphocytic leukemia.
[00480] The open-label, multicenter, global study is designed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics of intravenous durvalumab in subjects with certain B- cell malignancies. Approximately 253 patients may be enrolled in 4 treatment arms. The treatment arms include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab.
[00481] The study includes 3 sections corresponding to dose finding, dose confirmation, and dose expansion. The monotherapy treatment arm with durvalumab is not include a dose finding or dose expansion part. Patients receiving monotherapy durvalumab may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect) upon progression of disease. The primary endpoints of the study are (1) safety, (2) identification of recommended phase 2 dose (RP2D; phase 1, 3+3 design), and (3) preliminary overall response rate (ORR) measured by 2014 IWG criteria for lymphoma or 2008 IwCLL criteria for CLL.
[00482] Study Parameters:
[00483] Non-Tolerated Dose (NTD) - Phase 1 : a dose is considered to be a non-tolerated dose (NTD) if > 2 of 3 or 6 evaluable subjects in a dose level experience a Dose Limiting Toxicity (DLT).
[00484] Maximum Tolerated Dose (MTD)- Phase is defined as the highest dose level below the NTD with 0 of 3 or 1 of 6 (i.e., < 1/3 of subjects) evaluable subjects experiencing DLTs during the DLT evaluation period.
[00485] Overall Response Rate - Phase 2 is defined as the percent of subjects with best response of complete response (CR) or partial response (PR).
[00486] Secondary Outcome Measures are defined as the percent of subjects with best response of complete response (CR) or partial response (PR). [00487] Adverse events (AEs) of Phase 2 are coded according to Medical Dictionary for Drug Regulatory Activities (MedDRA) and classified using the NCI CTCAE. The incidence rates of AEs are tabulated by system organ class and preferred term. The incidence of AEs is also tabulated by severity within each system organ class and preferred term. The most severe grade of each preferred terms and adverse events of special interest for a subject are utilized for summaries of AEs by NCI CTCAE grade.
[00488] Duration of response (DoR)- Phasel/2 refers to the time from first Complete
Response (CR) or Partial Response (PR) to progressive disease (PD) or death.
[00489] Progression free survival (PFS) - Phase 1/2 refers to the time from first
Investigational product (IP) dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first.
[00490] Pharmacokinetics Parameters:
[00491] Blood samples are collected to assay concentrations of durvalumab and other combination agents (i.e., lenalidomide or ibrutinib).
[00492] Cmax refers to the maximum observed concentration. AUC refers to the area under the concentration-time curve. Tmax refers to the time to maximum concentration, tl/2 refers to the terminal half-life. Vz/F refers to the volume of distribution.
[00493] Conditions for investigation include Lymphoma, Chronic B-Cell Lymphocytic Leukemia.
[00494] Durvalumab (MEDI4736) will be supplied by Celgene Corporation in single use vials in single count cartons. Each 10R vial will be supplied as a vialed liquid solution containing 500 mg (nominal) of durvalumab at a concentration of 50 mg/mL. Durvalumab should be stored in accordance with the product label.
[00495] Lenalidomide is supplied by Celgene Corporation in appropriate strengths for oral administration. Investigational product is supplied in high-density polyethylene (HDPE) bottles containing a 21 day supply of lenalidomide. Lenalidomide is stored in accordance to the product label.
[00496] Rituximab is supplied outside the US and Canada by Celgene Corporation and labeled appropriately as investigational material for the study. For the US and Canada, rituximab is obtained according to local clinical study agreement and in accordance with local guidelines and the approved rituximab label or Pharmacy Manual.
[00497] Ibrutinib is supplied outside the US and Canada by Celgene Corporation and labeled appropriately as investigational material for the study. For the US and Canada, ibrutinib is obtained according to local clinical study agreement and in accordance with local guidelines and the approved Ibrutinib label (as 140 mg capsules) and the Pharmacy Manual.
[00498] Bendamustine is supplied outside the US or Canada by Celgene Corporation and labeled appropriately as investigational material for the study. For the US and Canada, bendamustine is obtained according to the local clinical study agreement and in accordance with local guidelines and the bendamustine lable and the Pharmacy Manual.
[00499] Local involved field radiation (IFRT) therapy may be added based on 2 Gy on each of 2 consecutive days to one tumor site in subjects who have with at least 1 measurable lesion (>1.5 cm and outside of the involved field which are irradiated) at the time of disease progression in Arm D (durvalumab monotherapy). This therapy is provided at the sites.
[00500] Following IFRT, the subject receives monthly durvalumab doses for up to 6 cycles based on investigator's medical judgment.
[00501] Treatment Arms:
[00502] Arm A: Durvalumab in combination with Lenalidomide and Rituximab: [00503] Subjects assigned to Arm A receive:
• Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13 (i.e., 12 months);
• Durvalumab at a fixed dose of 1500 mg administered as an IV infusion (250 mL) over approximately one hour in duration on Day 1 of Cycles 1 through 13.
• Durvalumab infusion is administered before any other IP on the days which more than one investigational treatment should be given (e.g., Day 1 of Cycles 1 through 13), and then lenalidomide administration and rituximab infusion are recommended to follow, respectively.
• Lenalidomide (PO) once daily on Days 1 to 21 (inclusive) of: • Cycles 1 through 13 in indolent Non-Hodgkin lymphoma (NHL) (i.e., FL or MZL) or
• All cycles of treatment period until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL
• Lenalidomide (PO) is administered after the durvalumab infusions on the days (e.g., Day 1 of Cycles 1 through 13) when more than one IP should be given.
• Lenalidomide 10 mg or 20 mg dose (depending on dose level in dose finding/confirmation part or renal function in dose expansion part) should be taken orally once daily, at approximately the same time each day. There is no requirement for taking lenalidomide with or without food, or with or without certain types of foods or liquids.
• Lenalidomide doses are taken from Days 1 through 21 of 28-day cycle. A 7-day rest period is required. A rest period may be extended due to toxicity as needed.
• Rituximab (IV) infusion on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 from Cycles 2 through 5.
• Rituximab administered at 375 mg/m2 every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of every 28-day cycle from Cycles 2 through 5.
• All dosage calculations for rituximab are based on the subject's BSA, using actual weight for calculations. This is determined during the Screening or on the first day of IP administration of Cycle 1 and is calculated using the subject's height and weight according to local pharmacy practice.
[00504] Arm B: Durvalumab in combination with Ibrutinib:
[00505] Subjects assigned to Arm B receive:
• Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13
• Ibrutinib (PO) continuous once daily until disease progression, unacceptable toxicity or discontinuation for any other reason • Ibrutinib (PO) administered after the durvalumab infusion on the days (e.g., Day 1 of Cycles 1 through 13) which both investigational treatments should be given.
• Ibrutinib, depending on dose level, 280 mg (2 x 140 mg capsules), 420 mg (3 x 140 mg capsules;) or 560 mg (4 x 140 mg capsules; is administered orally once daily with 8 ounces (approximately 240 mL) of water. The capsules are swallowed intact and subjects should not attempt to open capsules or dissolve them in water. Each dose of ibrutinib should be taken at least 30 minutes before eating or at least 2 hours after a meal, at approximately the same time each day.
• Ibrutinib dosing is continuous (without interruption) throughout the Treatment Period.
[00506] Arm C: Durvalumab in combination with Bendamustine and Rituximab: [00507] Subjects assigned to Arm C receive:
• Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13.
• Bendamustine (IV) infusion on Days 1 and 2 of Cycles 1 through 6.
• Bendamustine may be stopped after 4 cycles if the subject experiences a cumulative toxicity related to bendamustine and there is no clinical evidence of a favorable benefit to risk ratio for continuation of bendamustine treatment as per the investigator's medical judgment. If bendamustine is stopped earlier than 6 cycles, rituximab may be continued up to 6 cycles.
• Bendamustine will be administered as a 30-minute IV infusion at a dose of 90 or 70 mg/m2 (depending on dose level).
• Rituximab (IV) infusion on Day 2 Cycles 1 through 6.
• Rituximab dose is 375 mg/m2 in all cycles for Non-Hodgkin lymphoma (NHL). • Rituximab dose is 375 mg/m2 (Cycle 1; first dose) and 500 mg/m2 (subsequent doses: Cycle 2 through 6) for Chronic lymphocytic leukemia (CLL)..
[00508] Arm D: Durvalumab Monotherapy:
[00509] Subjects assigned to Arm D receive:
• Durvalumab (IV) infusion at a fixed dose of 1500 mg, on Day 1 of Cycles 1 through 13.
[00510] All treatment cycles in Arm D are 28 days.

Claims

WHAT IS CLAIMED:
1. A combination therapy comprising an immunomodulatory compound and one or more checkpoint inhibitors.
2. The combination therapy of claim 1, wherein said immunomodulatory compound has the formula:
Figure imgf000108_0001
wherein one of X and Y is C=0, the other of X and Y is C=0 or CH2, and R2 is hydrogen or methyl.
3. The combination therapy of claim 2, wherein said immunomodulatory compound has the formula:
3- (4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione;
4- (amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-l,3-dione; or
an optically pure isomer thereof.
4. The combination therapy of claim 1, wherein said immunomodulatory compound comprises 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione.
5. The combination therapy of claim 1, wherein said immunomodulatory compound comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-l,3-dione.
6. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-l/PD-Ll inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a B7 inhibitor, a T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an OX40 (CD 134) agonist, a GITR agonist, a CD 137 agonist, a CD40 agonist, and an IDO inhibitor.
7. The combination therapy of claim 6, wherein said checkpoint inhibitor comprises a CTLA-4 inhibitor.
8. The combination therapy of claim 6, wherein said checkpoint inhibitor comprises tremelimumab or ipilimumab.
9. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises a PD-1 inhibitor.
10. The combination therapy of claim 9, wherein said PD-1 inhibitor is selected from group consisting of nivolumab, pembrolizumab, CT-011, and AMP-224.
11. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises a PD-Ll inhibitor.
12. The combination therapy of claim 11, wherein said PD-Ll inhibitor selected from durvalumab or BMS-936559.
13. The combination therapy of claim 11, wherein said PD-Ll inhibitor is
durvalumab.
14. The combination of claim 11, wherein said PD-Ll inhibitor is durvalumab present at an amount of about 1500 mg.
15. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises a PD-L2 inhibitor.
16. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises a LAG-3 inhibitor.
17. The combination therapy of claim 16, wherein said LAG-3 inhibitor comprises IMP321 or BMS-986016.
18. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises a B7 inhibitor.
19. The combination therapy of claim 18, wherein said checkpoint inhibitor comprises a B7-H3 inhibitor or a B7-H4 inhibitor.
20. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor.
21. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises an OX40 (CD 134) agonist.
22. The combination therapy of claim 21, wherein said OX40 agonist is selected from anti-OX-40 or MEDI6469.
23. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises GITR agonist.
24. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises CD 137 agonist.
25. The combination therapy of claim 24, wherein said CD137 agonist is selected from urelumab or PF-05082566.
26. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises CD40 agonist.
27. The combination therapy of any one of claims 1 to 5, wherein said checkpoint inhibitor comprises IDO inhibitor.
28. The combination therapy of claim 27, wherein said IDO inhibitor is selected from INCB024360 or indoximod.
29. A combination therapy comprising a PD-L1 inhibitor and one or more secondary active agents for treating cancer.
30. The combination therapy of claim 29, wherein said PD-L1 inhibitor is durvalumab.
31. The combination therapy of claim 29, wherein said secondary active agent is selected from ibrutinib, rituximab, bendamustine, or a combination thereof.
32. The combination therapy of claim 29, comprising durvalumab in combination with ibrutinib.
33. The combination therapy of claim 29, comprising durvalumab in combination with rituximab and bendamustine.
34. The combination therapy of any one of claims 30 to 33, wherein said durvalumab is present at an amount of about 1500 mg.
35. The combination therapy of any one of claims 29 to 34, further comprising lenalidomide.
The combination therapy of claim 35, further comprising dexamethasone.
The combination therapy of any one of claims, wherein said combination therapy
(a) Durvalumab at an amount of about 1500 mg;
(b) Lenalidomide at an amount of about 10 to about 25 mg;
(c) Rituximab at an amount of about 375 mg/m2.
38. The combination therapy of claim 37, wherein said combination therapy is administered in 28 day cycles.
39. The combination of claim 38, wherein durvalumab is administered on day one of each cycle.
40. The combination of claim 38, wherein lenalidomide is administered on days 1-21 of each cycle.
41. The combination therapy of claim 38, wherein rituximab is administered on days 2, 8, 15, and 22 of the first cycle and on day 1 of each subsequent cycle.
42. The combination therapy of any one of claims 29 to 41, further comprising administering ibrutinib.
43. The combination therapy of claim 42, wherein said ibrutinib is administered at an amount of 280 mg, 420 mg, or 560 mg per day.
44. The combination therapy of any one of claims 29 to 43, further comprising administering bendamustine.
45. The combination therapy of claim 44, wherein bendamustine is administered at an amount of 90 or 70 mg/m2.
46. The combination therapy of claim 45, wherein bendamustine is administered on days 1 and 2 of each cycle.
47. A method of treating a patient having a hematological cancer, wherein said hematological cancer is diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), Hodgkin lymphoma (HL), follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), multiple myeloma (MM), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) by administering to the patient a therapeutically effective amount of a combination therapy of any one of claims 1 to 46.
48. The method of claim 47, wherein said hematological cancer is multiple myeloma.
-I l l-
49. The method of claim 48, wherein said multiple myeloma is relapsed multiple myeloma, refractory multiple myeloma, or newly diagnosed multiple myeloma.
50. The method of claim 47, wherein said hematological cancer is chronic lymphocytic leukemia.
51. The method of claim 47, wherein said patient has hematological cancer that is relapsed or refractory.
52. The method of claim 47, wherein said patient was treated with a prior treatment comprising a hypomethylating agent (HMA).
53. The method of claim 47, wherein said combination therapy reduces or eliminates minimal residual disease (MRD) state in said patient.
54. The method of claim 47, wherein said combination therapy is administered after administration of chemotherapy.
55. A method for treating chronic lymphocytic leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy of any one of claims 1 to 46 in combination with rituximab, ibrutinib, or bendamustine/rituximab.
56. The method of claim 55, wherein said combination therapy comprises durvalumab in combination with rituximab, ibrutinib, or bendamustine/rituximab.
57. The method of claim 55, wherein said combination therapy comprises an immunomodulatory compound in combination with durvalumab and one or more of rituximab, ibrutinib, or bendamustine/rituximab.
58. A method for treating lymphoma as described herein comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy of any one of claims 1 to 46 in combination with rituximab, ibrutinib, or bendamustine/rituximab.
59. The method of claim 58, wherein said combination therapy comprises durvalumab in combination with rituximab, ibrutinib, or bendamustine/rituximab.
60. The method of claim 58, wherein said combination therapy comprises an immunomodulatory compound in combination with durvalumab and one or more of rituximab, ibrutinib, or bendamustine/rituximab.
61. A method of treating, preventing, and/or managing myelodysplastic syndromes (MDS) by administering to a patient in need thereof the combination therapy of any one of claims 1 to 46.
62. The method of claim 61, wherein said MDS is high risk MDS.
63. The method of claim 61, wherein said patient has MDS that is relapsed or refractory.
64. The method of claim 61, wherein said patient was treating with a prior treatment comprising a hypomethylating agent (HMA).
65. The method of claim 61, wherein said combination therapy reduces or eliminates minimal residual disease (MRD) state in said patient.
66. The method of claim 61, wherein said combination therapy is administered after administration of chemotherapy.
67. The method of claim 61, wherein said combination therapy is administered before or after a stem cell transplant (SCT).
68. The method of claim 67, wherein said combination therapy is administered within 180 days of a SCT.
69. The method of claim 61, wherein said combination therapy is administered after a donor lymphocyte infusion (DLI).
70. The method of claim 61, wherein said administration reduces or eliminates the need for immunosuppressive drugs.
71. The method of claim 61, wherein said combination therapy prolongs complete remission of said MDS compared to treatment without said combination therapy.
72. The method of claim 47, 49, 55, 58, or 61, wherein said immunomodulatory compound of said combination therapy is administered daily for 21 consecutive days followed by a 7 day rest period in a 28 days cycle.
73. The method of claim 72, wherein said checkpoint inhibitor is administered on one or more days in a 28 days cycle.
74. The method of claim 73, wherein said checkpoint inhibitor is administered on day 1 of a 28 day cycle.
75. The method of claim 73, wherein said checkpoint inhibitor is a PD-L1 inhibitor.
76. The method of claim 75, wherein said PD-L1 inhibitor is an anti-PD-Ll antibody.
77. The method of claim 76, wherein said anti-PD-Ll antibody comprises
durvalumab.
78. The method of claim 72, wherein said 28 days cycle is repeated 1-12 times.
79. The method of claim 78, wherein said combination therapy is administered to said patient until disease progression or unacceptable toxicity.
80. The method of claim 47, 49, 55, 58, or 61, wherein said method further comprises administering a secondary active agent.
81. The method of claim 80, wherein said secondary active agent is administered weekly in a 28 days cycle.
82. The method of claim 81, wherein said secondary active agent is rituximab.
83. The method of claim 47, 49, 55, 58, or 61, wherein said immunomodulatory compound of said combination therapy is administered at an amount of about 5 to about 25 mg.
84. The method of claim 83, wherein said immunomodulatory compound is administered at about 10 mg or about 20 mg.
85. The method of claim 84, wherein said immunomodulatory compound is lenalidomide.
86. The method of claim 83, wherein said immunomodulatory compound is administered at about 0.5 mg or about 5 mg.
87. The method of claim 86, wherein said immunomodulatory compound is pomalidomide.
88. The method of claim 47, 49, 55, 58, or 61, wherein said checkpoint inhibitor is administered at an amount of about 500 mg to about 2000 mg.
89. The method of claim 86, wherein said checkpoint inhibitor is administered at an amount of about 1500 mg.
90. The method of claim 47, 49, 55, 58, or 61, wherein said patient has been previously treated for cancer.
91. The method of claim 47, 49, 55, 58, or 61, wherein said patient is non-responsive to at least one anti-cancer treatment.
92. The method of claim 47, 49, 55, 58, or 61, wherein said patient has a cancer that is resistance to at least one anti-cancer treatment.
93. The method of claim 47, 49, 55, 58, or 61, wherein said patient has undergone at least one surgery to treat said cancer.
94. The method of any of of claims 1 to 91, wherein the method further comprises assessing treatment with a combination therapy of claim 1, by determining one or more of inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including expression levels of checkpoint proteins as identified herein), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), or increased Overall Survival (OS).
95. The method of claim 92, wherein the treatment is assessed by one or more clinical endpoints selected from positive tumor response, complete response, partial response or stable disease, increased survival without tumor progression, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and increased Overall Survival (OS).
96. A method for increasing the overall survival, objective response rate, time to progression, progression-free survival or time-to-treatment failure of a patient having a hematological cancer, the method comprising administering an effective amount of a
combination therapy of any one of claims 1 to 46.
PCT/US2016/053900 2015-09-28 2016-09-27 Combination therapy for treatment of hematological cancers and solid tumors WO2017058754A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562233960P 2015-09-28 2015-09-28
US62/233,960 2015-09-28
US201662307314P 2016-03-11 2016-03-11
US62/307,314 2016-03-11

Publications (1)

Publication Number Publication Date
WO2017058754A1 true WO2017058754A1 (en) 2017-04-06

Family

ID=58424230

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/053900 WO2017058754A1 (en) 2015-09-28 2016-09-27 Combination therapy for treatment of hematological cancers and solid tumors

Country Status (1)

Country Link
WO (1) WO2017058754A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018204427A1 (en) * 2017-05-01 2018-11-08 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
US11066475B2 (en) 2017-11-01 2021-07-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
WO2022029429A1 (en) * 2020-08-05 2022-02-10 Vicore Pharma Ab New injectable formulations comprising immunomodulator drug
US11306144B2 (en) 2017-08-25 2022-04-19 Five Prime Therapeutics, Inc. B7-H4 antibodies and methods of use thereof
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
US11851679B2 (en) 2017-11-01 2023-12-26 Juno Therapeutics, Inc. Method of assessing activity of recombinant antigen receptors
US11939383B2 (en) 2018-03-02 2024-03-26 Five Prime Therapeutics, Inc. B7-H4 antibodies and methods and use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150118222A1 (en) * 2013-10-25 2015-04-30 Pharmacyclics, Inc. Treatment using bruton's tyrosine kinase inhibitors and immunotherapy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150118222A1 (en) * 2013-10-25 2015-04-30 Pharmacyclics, Inc. Treatment using bruton's tyrosine kinase inhibitors and immunotherapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MILLWARD ET AL.: "Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours", BRITISH JOURNAL OF CANCER, vol. 108, 2013, pages 1998 - 2004, XP055365870 *
PAGE ET AL.: "Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions", CURR ONCOL REP ., vol. 15, no. 5, 2013, pages 500 - 508, XP055385285 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018204427A1 (en) * 2017-05-01 2018-11-08 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
EP4327878A3 (en) * 2017-05-01 2024-05-01 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
US11306144B2 (en) 2017-08-25 2022-04-19 Five Prime Therapeutics, Inc. B7-H4 antibodies and methods of use thereof
US11814431B2 (en) 2017-08-25 2023-11-14 Five Prime Therapeutics, Inc. B7-H4 antibodies and methods of use thereof
US11066475B2 (en) 2017-11-01 2021-07-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
US11851679B2 (en) 2017-11-01 2023-12-26 Juno Therapeutics, Inc. Method of assessing activity of recombinant antigen receptors
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
US11304961B2 (en) 2017-12-18 2022-04-19 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
US11939383B2 (en) 2018-03-02 2024-03-26 Five Prime Therapeutics, Inc. B7-H4 antibodies and methods and use thereof
WO2022029429A1 (en) * 2020-08-05 2022-02-10 Vicore Pharma Ab New injectable formulations comprising immunomodulator drug

Similar Documents

Publication Publication Date Title
US10973822B2 (en) Combination therapy for treatment of hematological cancers and solid tumors
JP6348192B2 (en) Method for treating cancer using 3- (5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl) -piperidine-2,6-dione
WO2017058754A1 (en) Combination therapy for treatment of hematological cancers and solid tumors
US20200138804A1 (en) Methods for treating cancer
JP5916977B2 (en) Method of using 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione for the treatment of certain leukemias
EP3644999B1 (en) Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide
US20230301979A1 (en) Combinations for the treatment of cancer
EP3888648A1 (en) Treatment of cancer by combination of immune checkpoint inhibitor and folfirinox therapy
CN114845716A (en) Prediction of clinical sensitivity to 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide using biomarkers
JP2022554346A (en) Combination with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide therapy
KR20220154175A (en) Combination therapy for acute myeloid leukemia
NZ614493B2 (en) Methods of treating cancer using 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16852387

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16852387

Country of ref document: EP

Kind code of ref document: A1