WO2018156680A1 - Treatment of refractory of relapsed hematological cancer with durvalumab - Google Patents
Treatment of refractory of relapsed hematological cancer with durvalumab Download PDFInfo
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- WO2018156680A1 WO2018156680A1 PCT/US2018/019096 US2018019096W WO2018156680A1 WO 2018156680 A1 WO2018156680 A1 WO 2018156680A1 US 2018019096 W US2018019096 W US 2018019096W WO 2018156680 A1 WO2018156680 A1 WO 2018156680A1
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- durvalumab
- hematological cancer
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- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- 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
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/804—Blood cells [leukemia, lymphoma]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
Definitions
- hematological cancer in a subject who has failed treatment with a CD19-directed CAR-T cell therapy comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab.
- 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.
- the two 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
- T cell activation induces expression of CTLA-4 on T lymphocytes, thereby inhibits further T cell activation and proliferation.
- anti-CTLA-4 antibodies can directly activate CD4(+) and CD8(+) effector cells and generate anti-tumor responses.
- PD-1 signaling plays an important role in promoting regulatory T cell (Treg) function and preventing auto-immunity.
- Teg regulatory T cell
- 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.
- 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.
- a blood cancer or hematological malignancy is a type of malignant cancer that originates, affects, or involves the blood, bone marrow, or lymph nodes. These cancers include leukemia, lymphomas, and myelomas. These particular types of cancers can arise as defected mature cell types that have differentiated from hematopoietic precursor cells (often in the bone marrow) and begin to quickly proliferate through the bloodstream, where it can then often infiltrate other organs and tissues. Others can involve the formation of tumors from lymphoblasts within the lymphoid tissue.
- lymphomas The pathogenesis of lymphomas involves the accumulation of multiple genetic lesions affecting proto-oncogenes and tumor suppressor genes.
- the lymph node The lymph node
- microenvironment which includes stromal cells, macrophages, regulatory T-cells, and the lymph node vasculature, has been implicated in the promotion of lymphomagenesis.
- Hodgkin lymphoma formerly called Hodgkin's disease, arises from germinal center or post-germinal center B-cells.
- HL has a unique cellular composition, containing a minority of neoplastic cells (Reed- Sternberg cells and their variants) in an inflammatory background.
- HL is a B-cell lymphoma that accounts for approximately 10% of all lymphomas in economically advanced countries. This amounts to approximately 9,050 new cases and about 1, 150 deaths due to HL in the US annually. The incidence in Europe is approximately 2.4 cases per 100,000 persons.
- NHL Non-Hodgkin lymphoma
- NHL Non-Hodgkin lymphoma
- follicular lymphoma mantle cell lymphoma
- Burkitt lymphoma Burkitt lymphoma
- CLL Chronic lymphocytic leukemia
- Acute lymphoblastic leukemia also known as acute lymphocytic leukemia or acute lymphoid leukemia (ALL) is an acute form of leukemia. ALL is most common in childhood, with a peak incidence at 2-5 years of age and another peak in old age. About 6,000 cases are reported in the United States every year.
- AML Acute myeloid leukemia
- ANLL acute nonlymphocytic leukemia
- AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells.
- AML is the most common acute leukemia affecting adults, and its incidence increases with age.
- Chronic myelogenous (or myeloid or myelocytic) leukemia is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. In western countries, it accounts for 15-20% of all adult leukemia and 14% of leukemia overall
- MDS Myelodysplastic syndromes
- the overall incidence of MDS in the United States is estimated at close to four cases per 100,000 people, with as many as 20,000 to 30,000 people diagnosed annually.
- MDS myelodysplastic syndromes
- Treatment for MDS includes blood transfusion, growth factors, chemotherapy, and bone marrow transplant or stem cell transplant. Many treatments can place MDS in remission but treatment failure and possible recurrence of MDS exist with few options available following treatment.
- MPD Myeloproliferative disorders
- hematological cancer in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- Also provided herein is a method of treating, preventing, or managing lymphoma in a subject, comprising administering to the subject in need thereof a
- a method of treating, preventing, or managing non-Hodgkin lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing diffuse large B-cell lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing primary mediastinal B-cell lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing follicular lymphoma in a subject comprising administering to the subject in need thereof a
- a method of treating, preventing, or managing transformed follicular lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing mantle cell lymphoma in a subject comprising administering to the subject in need thereof a
- a method of treating, preventing, or managing leukemia in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing chronic lymphocytic leukemia in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing Richter's transformation in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing acute lymphoblastic leukemia in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
- 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 the disease, disorder or condition, or the symptom.
- administration of the substance typically occurs before the onset of the disease, disorder or condition, or the symptom.
- subject refers to an animal, including, but not limited to, a primate
- subject e.g., human
- cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse e.g., cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
- subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
- treat means to include alleviating or abrogating a disease, disorder, or condition, or one or more of the symptoms associated with the disease, disorder, or condition; or alleviating or eradicating the cause(s) of the disease, disorder, or condition itself.
- prevent are meant to include a method of delaying and/or precluding the onset of a disease, disorder, or condition, and/or its attendant symptoms; barring a subject from acquiring a disease, disorder, or condition; or reducing a subject' s risk of acquiring a disease, disorder, or condition.
- the term "manage,” “managing,” or “management” refers to preventing or slowing the progression, spread or worsening of a disease, disorder or condition, or one or more symptoms thereof.
- the beneficial effects that a subject derives from a prophylactic or therapeutic agent may not result in a cure of the disease, disorder or condition.
- terapéuticaally effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease, disorder, or condition being treated.
- therapeutically effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease, disorder, or condition being treated.
- an “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
- a biological molecule e.g., a protein, enzyme, RNA, or DNA
- cell tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
- prophylactically effective amount is meant to include the amount of a compound that, when administered, is sufficient to inhibit or reduce a symptom of the disease, disorder, or condition being treated, or to prevent recurrence of the disease, disorder, or condition being treated.
- the term "therapy” refers to a 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 term “therapies” or “therapy” refers 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 a medical personnel.
- 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%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
- cancer or “cancerous” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth.
- hematological cancer refers to blood-borne cancer (e.g., multiple myeloma, lymphoma, and leukemia).
- provided herein is a method of treating, preventing, or managing a hematological cancer in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- the hematological cancer is myeloma, lymphoma, or leukemia.
- the hematological cancer is myeloma. In another embodiment, the hematological cancer is multiple myeloma (MM). In yet another embodiment, the hematological cancer is refractory MM. In still another embodiment, the hematological cancer is relapsed MM.
- the hematological cancer is leukemia.
- the hematological cancer is acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), Richter's transformation, hairy cell leukemia, myelodysplasia, a myeloproliferative disorder, chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, or B-cell acute lymphoblastic leukemia.
- AML acute myelogenous leukemia
- ALL acute lymphocytic leukemia
- CLL chronic lymphocytic leukemia
- Richter's transformation hairy cell leukemia, myelodysplasia, a myeloproliferative disorder, chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), human
- hematological cancer is adult T-cell leukemia. In yet another embodiment, the hematological cancer is CLL. In yet another embodiment, the hematological cancer is Richter's
- the hematological cancer is hairy cell leukemia. In yet another embodiment, the hematological cancer is myelodysplasia. In yet another embodiment, the hematological cancer is a myeloproliferative disorder. In yet another embodiment, the hematological cancer is CML. In yet another embodiment, the
- hematological cancer is MDS. In yet another embodiment, the hematological cancer is HTLV-1 leukemia. In yet another embodiment, the hematological cancer is mastocytosis. In still another embodiment, the hematological cancer is B-cell acute lymphoblastic leukemia.
- the leukemia is CLL, ALL, or Richter's transformation.
- the hematological cancer is lymphoma.
- the hematological cancer is diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus- type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, transformed follicular lymphoma, small lymphocytic lymphoma, T- cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma, or ALK-positive large B-cell lymphoma.
- DLBCL diffuse large B-cell
- the hematological cancer is DLBCL. In yet another embodiment, the hematological cancer is B- cell immunoblastic lymphoma. In yet another embodiment, the hematological cancer is small non-cleaved cell lymphoma. In yet another embodiment, the hematological cancer is HTLV- 1 leukemia/lymphoma. In yet another embodiment, the hematological cancer is adult T-cell lymphoma. In yet another embodiment, the hematological cancer is MCL. In yet another embodiment, the hematological cancer is HL. In yet another embodiment, the hematological cancer is NHL. In yet another embodiment, the hematological cancer is AIDS-related lymphoma.
- the hematological cancer is follicular lymphoma. In yet another embodiment, the hematological cancer is transformed follicular lymphoma. In yet another embodiment, the hematological cancer is small lymphocytic lymphoma. In yet another embodiment, the hematological cancer is T-cell/histiocyte rich large B-cell lymphoma. In yet another embodiment, the hematological cancer is transformed lymphoma. In yet another embodiment, the hematological cancer is primary mediastinal (thymic) large B-cell lymphoma. In yet another embodiment, the hematological cancer is splenic marginal zone lymphoma. In yet another embodiment, the hematological cancer is nodal marginal zone lymphoma. In still another embodiment, the hematological cancer is ALK-positive large B-cell lymphoma.
- the hematological cancer is non-Hodgkin lymphoma.
- the non-Hodgkin lymphoma is diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, transformed follicular lymphoma, or mantle cell lymphoma.
- provided herein is a method of treating, preventing, or managing leukemia in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing CLL in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing Richter's transformation in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing ALL in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing non-Hodgkin lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing diffuse large B-cell lymphoma in a subject comprising
- a method of treating, preventing, or managing primary mediastinal B-cell lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing follicular lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing transformed follicular lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- a method of treating, preventing, or managing mantle cell lymphoma in a subject comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
- the hematological cancer is refractory. In certain embodiments, the hematological cancer is relapsed. In certain embodiments, the
- hematological cancer is metastatic. In certain embodiments, the hematological cancer is drug-resistant.
- the subject having the hematological cancer has failed prior treatment with JCAR014 therapy. In another embodiment, the subject having the hematological cancer has failed prior treatment with JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has failed prior treatment with one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has disease progression during or following a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression during or following JCAR014 therapy. In another embodiment, the subject having the hematological cancer has disease progression during or following JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression during or following JCAR017 therapy. In yet another embodiment, the subject having the
- hematological cancer has disease progression during or following tisagenlecleucel (CTL019) therapy.
- the subject having the hematological cancer has disease progression during or following axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has disease progression during or following one of CD19-directed CAR-T cell therapies disclosed in US 7,446, 190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has disease progression within 24 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 24 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has disease progression within 24 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 24 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 24 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has disease progression within 24 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has disease progression within 24 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has disease progression within 18 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 18 months after JCAR014 therapy. In another embodiment, the subject having the
- hematological cancer has disease progression within 18 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has disease progression within 18 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has disease progression within 12 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 12 months after JCAR014 therapy. In another embodiment, the subject having the
- hematological cancer has disease progression within 12 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 12 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 12 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 12 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has disease progression within 12 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has disease progression within 8 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 8 months after JCAR014 therapy. In another embodiment, the subject having the
- hematological cancer has disease progression within 8 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 8 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 8 months after tisagenlecleucel
- the subject having the hematological cancer has disease progression within 8 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease
- the subject having the hematological cancer has disease progression within 6 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 6 months after JCAR014 therapy. In another embodiment, the subject having the
- hematological cancer has disease progression within 6 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 6 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 6 months after tisagenlecleucel
- the subject having the hematological cancer has disease progression within 6 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has disease progression within 6 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse during or following a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse during or following JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse during or following JCAR015 therapy. In yet another embodiment, the subject having the
- hematological cancer has a relapse during or following JCAR017 therapy.
- the subject having the hematological cancer has a relapse during or following tisagenlecleucel (CTL019) therapy.
- the subject having the hematological cancer has a relapse during or following axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has a relapse during or following one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse within 24 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 24 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has a relapse within 24 months after axicabtagene ciloleucel (KTE- C19) therapy.
- the subject having the hematological cancer has a relapse within 24 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse within 18 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 18 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has a relapse within 18 months after axicabtagene ciloleucel (KTE- C19) therapy.
- the subject having the hematological cancer has a relapse within 18 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse within 12 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 12 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has a relapse within 12 months after axicabtagene ciloleucel (KTE- C19) therapy.
- the subject having the hematological cancer has a relapse within 12 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse within 8 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 8 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has a relapse within 8 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has a relapse within 8 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the subject having the hematological cancer has a relapse within 6 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 6 months after tisagenlecleucel (CTL019) therapy.
- CTL019 tisagenlecleucel
- the subject having the hematological cancer has a relapse within 6 months after axicabtagene ciloleucel (KTE-C19) therapy.
- the subject having the hematological cancer has a relapse within 6 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the hematological cancer is refractory to a CD 19- directed CAR-T cell therapy. In one embodiment, the hematological cancer is refractory to JCAR014 therapy. In another embodiment, the hematological cancer is refractory to
- the hematological cancer is refractory to JCAR017 therapy.
- the hematological cancer is refractory to tisagenlecleucel (CTL019) therapy.
- the hematological cancer is refractory to axicabtagene ciloleucel (KTE-C19) therapy.
- the hematological cancer is refractory to one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
- the therapeutically effective amount is ranging from about 1 mg/kg every four weeks to about 50 mg/kg every week. In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every four weeks. In certain embodiments, the therapeutically effective amount is ranging from about 5 to about 25 mg/kg every four weeks. In certain embodiments, the therapeutically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every four weeks.
- the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every three weeks. In certain embodiments, the therapeutically effective amount is ranging from about 5 to about 25 mg/kg every three weeks. In certain embodiments, the therapeutically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every three weeks.
- the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every two weeks. In certain embodiments, the therapeutically effective amount is ranging from about 2 to about 20 mg/kg every two weeks. In certain embodiments, the therapeutically effective amount is about 2, about 5, about 10, about 15, or about 20 mg/kg every two weeks.
- the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every week. In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 20 mg/kg every week. In certain embodiments, the therapeutically effective amount is about 1, about 2, about 5, about 10, about 15, or about 20 mg/kg every week.
- the therapeutically effective amount is ranging from about 100 mg every four weeks to about 5,000 mg every week. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 5,000 mg every four weeks. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 2,500 mg every four weeks. In certain embodiments, the therapeutically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every four weeks.
- the therapeutically effective amount is ranging from about 500 to about 5,000 mg every three weeks. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 2,500 mg every three weeks. In certain embodiments, the therapeutically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every three weeks.
- the therapeutically effective amount is ranging from about 200 to about 5,000 mg every two weeks. In certain embodiments, the therapeutically effective amount is ranging from about 200 to about 2,000 mg every two weeks. In certain embodiments, the therapeutically effective amount is about 200, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg every two weeks.
- the therapeutically effective amount is ranging from about 100 to about 5,000 mg every week. In certain embodiments, the therapeutically effective amount is ranging from about 100 to about 1,000 mg every week. In certain embodiments, the therapeutically effective amount is about 100, about 200, about 500, about 750, or about 1,000 mg every week.
- the prophylactically effective amount is ranging from about 1 mg/kg every four weeks to about 50 mg/kg every week. In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every four weeks. In certain embodiments, the prophylactically effective amount is ranging from about 5 to about 25 mg/kg every four weeks. In certain embodiments, the prophylactically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every four weeks.
- the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every three weeks. In certain embodiments, the prophylactically effective amount is ranging from about 5 to about 25 mg/kg every three weeks. In certain embodiments, the prophylactically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every three weeks.
- the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every two weeks. In certain embodiments, the prophylactically effective amount is ranging from about 2 to about 20 mg/kg every two weeks. In certain embodiments, the prophylactically effective amount is about 2, about 5, about 10, about 15, or about 20 mg/kg every two weeks.
- the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every week. In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 20 mg/kg every week. In certain embodiments, the prophylactically effective amount is about 1, about 2, about 5, about 10, about 15, or about 20 mg/kg every week. [0088] In certain embodiments, the prophylactically effective amount is ranging from about 100 mg every four weeks to about 5,000 mg every week. In certain embodiments, the prophylactically effective amount is ranging from about 500 to about 5,000 mg every four weeks. In certain embodiments, the prophylactically effective amount is ranging from about 500 to about 2,500 mg every four weeks. In certain embodiments, the prophylactically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every four weeks.
- the prophylactically effective amount is ranging from about 500 to about 5,000 mg every three weeks. In certain embodiments, the
- prophylactically effective amount is ranging from about 500 to about 2,500 mg every three weeks. In certain embodiments, the prophylactically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every three weeks.
- the prophylactically effective amount is ranging from about 200 to about 5,000 mg every two weeks. In certain embodiments, the prophylactically effective amount is ranging from about 200 to about 2,000 mg every two weeks. In certain embodiments, the prophylactically effective amount is about 200, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg every two weeks.
- the prophylactically effective amount is ranging from about 100 to about 5,000 mg every week. In certain embodiments, the prophylactically effective amount is ranging from about 100 to about 1,000 mg every week. In certain embodiments, the prophylactically effective amount is about 100, about 200, about 500, about 750, or about 1,000 mg every week.
- durvalumab is administered cyclically. In certain embodiments, durvalumab is administered in a 28-day cycle. In certain embodiments, durvalumab is administered twice in a 28-day cycle. In certain embodiments, durvalumab is administered every two weeks in a 28-day cycle. In certain embodiments, durvalumab is administered on days 1 and 15 in a 28-day cycle. In certain embodiments, durvalumab is administered once in a 28-day cycle. In certain embodiments, durvalumab is administered once on day 1 in a 28-day cycle. In certain embodiments, durvalumab is administered once on day 15 in a 28-day cycle.
- durvalumab is administered twice in 28 days, followed by once every 28 days. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days, followed by once every 28 days. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days in an amount of about 10 mg/kg, followed by once every 28 days in an amount of about 20 mg/kg. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days in an amount of about 0.75 g, followed by once every 28 days in an amount of about 1.5 g.
- durvalumab is administered parenterally. In certain embodiments, durvalumab is administered intravenously. In certain embodiments, durvalumab is administered via an intravenous infusion. In certain embodiments, durvalumab is administered via an intravenous infusion over 60 minutes.
- the methods provided herein encompass treating a subject regardless of subject's age, although some diseases or disorders are more common in certain age groups.
- the subject is a mammal. In certain embodiments, the subject is a human.
- Durvalumab can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a disease, disorder, or condition described herein.
- the term "in combination” includes the use of more than one therapy ⁇ e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies ⁇ e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
- a first therapy ⁇ e.g., a prophylactic or therapeutic agent such as durvalumab
- a prophylactic or therapeutic agent such as durvalumab
- a second therapy ⁇ e.g., a prophylactic or therapeutic agent
- the route of administration of durvalumab is independent of the route of administration of a second therapy.
- the second therapy 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.
- each method provided herein may independently, further comprise the step of administering a second therapeutic agent ⁇ i.e., a second therapy).
- Examples of second therapeutic agents include, but are not limited to:
- ABRAXANE® ace-11; acivicin; aclambicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine;
- anastrozole anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;
- batimastat batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
- calusterone caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride;
- etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; benzrabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; maso
- methotrexate methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane;
- mitoxantrone hydrochloride mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;
- vincristine sulfate vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
- second therapeutic agents include, but are not limited to: 0-epi-l,25 dihy droxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
- amidox amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix;
- azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
- benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
- carboxamide-amino-triazole carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
- combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
- dioxamycin diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
- doxorubicin doxorubicin
- droloxifene dronabinol
- duocarmycin SA ebselen
- ecomustine ebselen
- ebselen ecomustine
- edelfosine edrecolomab
- eflornithine elemene
- emitefur epirubicin
- epristeride estramustine analogue
- estrogen agonists estrogen antagonists
- etanidazole etoposide phosphate
- exemestane exemestane
- fluasterone fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;
- gelatinase inhibitors include gemcitabine; glutathione inhibitors; hepsulfam; heregulin;
- hexamethylene bisacetamide hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., GLEEVEC®), imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;
- lanreotide leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
- losoxantrone loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;
- metoclopramide MIF inhibitor
- mifepristone miltefosine
- mirimostim mitoguazone
- mitolactol mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin;
- N-substituted benzamides N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (GENASENSE®); 0 6 -benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmito
- phenazinomycin phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal;
- protein tyrosine phosphatase inhibitors protein tyrosine phosphatase inhibitors
- purine nucleoside phosphorylase inhibitors purine nucleoside phosphorylase inhibitors
- purpurins pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
- ribozymes RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl;
- senescence derived inhibitor 1 sense oligonucleotides
- signal transduction inhibitors signal transduction inhibitors
- spongistatin 1 squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine;
- tamoxifen methiodide tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;
- thaliblastine thiocoraline
- thrombopoietin thrombopoietin mimetic
- thymalfasin thymalfasin
- thymopoietin receptor agonist thymotrinan
- thyroid stimulating hormone tin ethyl etiopurpurin
- tirapazamine titanocene bichloride
- topsentin toremifene
- translation inhibitors tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;
- turosteride tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
- the active agents of a combination therapy provided herein are administered cyclically to the subject.
- a cycling therapy involves the
- a 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 phase 2, multicenter, single-arm, open-label study is conducted to evaluate the efficacy and safety of durvalumab in subjects with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL) who have failed (progressed, relapsed, or have not responded to) prior treatment with CD19-directed chimeric antigen receptor (CAR) T cells.
- NDL non-Hodgkin lymphoma
- CLL chronic lymphocytic leukemia
- ALL acute lymphoblastic leukemia
- a primary outcome measure for NHL is an overall response rate in NHL subjects who have failed prior treatment with JCAR017.
- the number of subjects with best disease response of complete response (CR) or partial response (PR) during durvalumab treatment is determined according to the International Working Group (IWG) Response Criteria for Malignant Lymphoma (the Lugano Classification) or the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Response Criteria.
- IWG International Working Group
- a secondary outcome measure for the NHL subjects who have failed prior treatment with JCAR017 is a complete response rate (CRR). The percentage of the NHL subjects achieved CR following durvalumabe administration is determined.
- a primary outcome measure for NHL is an overall response rate in NHL subjects who have failed prior treatment with a CD-19-directed CAR T cell therapy other than JCAR017.
- the percentage of subjects with best disease response of complete response (CR) or partial response (PR) during durvalumab treatment is determined according to the IWG Response Criteria for Malignant Lymphoma (the Lugano Classification) or the IWCLL Response Criteria.
- a secondary outcome measure for the NHL subjects who have failed prior treatment with a CD-19-directed CAR T cell therapy other than JCAR017 is a CRR.
- the percentage of NHL subjects achieved CR following durvalumabe administration is determined.
- a primary outcome measure for CLL is an overall response rate in CLL subjects who have failed prior treatment with JCAR017. The percentage of subjects with best disease response of CR, complete response with incomplete bone receovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL) is determined.
- a secondary outcome measure for CLL is a CRR.
- the percentage of CLL subjects achieved CR following durvalumabe administration is determined.
- a primary outcome measure for ALL is an overall response rate in ALL subjects who have failed prior treatment with JCAR017. The percentage of subjects with best disease response of CR or CRi is determined.
- a secondary outcome measure for ALL is a CRR. The percentage of ALL subjects achieved CR following durvalumabe administration is determined.
- Percentages of subjects achieving a CR/CRi and/or minimal residual disease (MRD) negativity as well as duration of response (DoR), progression-free survival (PFS), and overall survival (OS) for patients with NHL, CLL, and ALL are determined.
- the percentage of CLL subjects achieving MRD negativity following durvalumab administration is determined.
- the percentage of ALL subjects achieving MRD negativity following durvalumab administration is determined.
- Duration of response i.e., the time from first CR or PR to progressive disease
- PD PD or death
- Duration of response i.e., the time from first CR, CRi, nPR, PR, or PRL to PD or death
- CLL subjects i.e., the time from first CR or CRi to PD or death
- ALL subjects i.e., ALL subjects.
- Progression-free survival i.e., the time from first durvalumab infusion to the first documentation of progressive disease, disease relapse, or death, whichever occurs first
- Overall survival i.e., the time from the furvalumab infusion to time of death due to any cause
- the study enrolls approximately 88 subjects (> 18 years of age), including three cohorts of subjects, separated by disease type, who have failed prior treatment with JCAR017.
- the subjects In Cohort 1 (post JCAR017), the subjects have NHL, including diffuse large B- cell lymphoa (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), transformed FL (tFL), and mantle cell lymphoma (MCL).
- LLBCL diffuse large B- cell lymphoa
- PMBCL primary mediastinal B-cell lymphoma
- FL follicular lymphoma
- tFL transformed FL
- MCL mantle cell lymphoma
- MCL mantle cell lymphoma
- subjects in Cohort 4 are those, irrespective of disease type, who have failed prior treatment with a CD19-directed CAR T cell therapy.
- the subjects in Cohort 4 are those with NHL, including DLBCL, PMBCL, FL, tFL, or MCL after any previous CD19-directed CAR T cells treatment other than JCAR017.
- the subjects in the study have progressive disease after the most recent therapy with JCAR017 or other anti CD- 19 directed chimeric antigen receptor T cells, or relapse to the most recent therapy with JCAR017 or other anti CD- 19 directed chimeric antigen receptor T cells.
- In vivo expansion of CAR T cells after infusion is mandatory.
- PD or relapse is defined according to: (i) the TvVG Response Criteria for Malignant Lymphoma (the Lugano Classification) for NHL; (ii) the TvVCLL Response Criteria for CLL; and (iii) National Comprehensive Cancer Network (NCCN) guidelines for ALL.
- the subjects in the study meet criteria for needed treatment according to the European Socieity for Medical Oncology (ESMO) Clinical Practice Guidelines, National Comprehensive Cancer Network.
- the subject in the study have a Eastern Cooperative Onlogy Group (ECOG) performance-status core of 2 or less. Also toxicities resulting from CD19-directed CAR T cell therapy (including cytokine release syndrome (CRS) and/or nuerotoxi cities) must have resolved or stabilized to ⁇ Grade 1.
- Each treatment cycle consists of 28 days. Subjects receive durvalumab at a dose of 750 mg on Days 1 and 15 of Cycle 1, followed by a dose of 1,500 mg once every four weeks (Q4 weeks or Q4wk) for up to 12 additional cycles.
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Abstract
Provided herein is a method of treating, preventing, or managing a hematological cancer in a subject having failed a CD19-directed CAR-T cell therapy, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab.
Description
TREATMENT OF REFRACTORY OR RELAPSED HEMATOLOGICAL CANCER
WITH DURVALUMAB
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the priority to U.S. Provisional Application No.
62/462,265, filed February 22, 2017; the disclosure of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein is a method of treating, preventing, or managing
hematological cancer in a subject who has failed treatment with a CD19-directed CAR-T cell therapy, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab.
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. The two 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 anti-tumor responses. Wolchok et al., Oncologist 2008, 73(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.
[0005] 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. U.S.A. 2002, 99, 12293-12997. Early-phase clinical trials of anti-PD-1 antibodies have shown promising anti-tumor 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.
[0006] A blood cancer or hematological malignancy is a type of malignant cancer that originates, affects, or involves the blood, bone marrow, or lymph nodes. These cancers include leukemia, lymphomas, and myelomas. These particular types of cancers can arise as defected mature cell types that have differentiated from hematopoietic precursor cells (often in the bone marrow) and begin to quickly proliferate through the bloodstream, where it can then often infiltrate other organs and tissues. Others can involve the formation of tumors from lymphoblasts within the lymphoid tissue.
[0007] The pathogenesis of lymphomas involves the accumulation of multiple genetic lesions affecting proto-oncogenes and tumor suppressor genes. The lymph node
microenvironment, which includes stromal cells, macrophages, regulatory T-cells, and the lymph node vasculature, has been implicated in the promotion of lymphomagenesis.
[0008] Hodgkin lymphoma (HL), formerly called Hodgkin's disease, arises from germinal center or post-germinal center B-cells. HL has a unique cellular composition, containing a minority of neoplastic cells (Reed- Sternberg cells and their variants) in an inflammatory background. HL is a B-cell lymphoma that accounts for approximately 10% of all lymphomas in economically advanced countries. This amounts to approximately 9,050
new cases and about 1, 150 deaths due to HL in the US annually. The incidence in Europe is approximately 2.4 cases per 100,000 persons.
[0009] Non-Hodgkin lymphoma (NHL), which often refers to group of lymphomas except HL, is more common than HL. About 90% of lymphomas are NHL. Common subtypes of NHL include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Burkitt lymphoma. In 2015, it is estimated that there will be 71,850 new cases of NHL and an estimated 19,790 people will die from this disease annually in the U.S.
[0010] Chronic lymphocytic leukemia (CLL) is the most common leukemia in North
America and Europe with an incidence of 4.0 cases per 100,000 persons per year and has a median age of diagnosis of 72 years. It consists of an accumulation of mature B-cells typically cluttering in marrow, blood and lymphoid organs with a unique CD 19+, CD5+, and CD23+ phenotype.
[0011] Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia (ALL), is an acute form of leukemia. ALL is most common in childhood, with a peak incidence at 2-5 years of age and another peak in old age. About 6,000 cases are reported in the United States every year.
[0012] Acute myeloid leukemia (AML), also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL), is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age.
[0013] Chronic myelogenous (or myeloid or myelocytic) leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. In western countries, it accounts for 15-20% of all adult leukemia and 14% of leukemia overall
(including the pediatric population).
[0014] Myelodysplastic syndromes (MDS) are hematological medical conditions with ineffective production of all blood cells. The overall incidence of MDS in the United States is estimated at close to four cases per 100,000 people, with as many as 20,000 to 30,000 people diagnosed annually. There are several different types of MDS which can be further
classified as low risk MDS or high risk MDS - depending on the progression and severity of the disease. Treatment for MDS includes blood transfusion, growth factors, chemotherapy, and bone marrow transplant or stem cell transplant. Many treatments can place MDS in remission but treatment failure and possible recurrence of MDS exist with few options available following treatment.
[0015] Myeloproliferative disorders (MPD) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia.
[0016] Thus, there is an unmet need for effective treatment for hematological cancers to reduce treatment failure and to reduce or eliminate recurrence or development of resistance to an anticancer therapy.
SUMMARY OF THE DISCLOSURE
[0017] Provided herein is a method of treating, preventing, or managing a
hematological cancer in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0018] Also provided herein is a method of treating, preventing, or managing lymphoma in a subject, comprising administering to the subject in need thereof a
therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0019] Additionally provided herein is a method of treating, preventing, or managing non-Hodgkin lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0020] Furthermore, provided herein is a method of treating, preventing, or managing diffuse large B-cell lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0021] Provided herein is a method of treating, preventing, or managing primary
mediastinal B-cell lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0022] Provided herein is a method of treating, preventing, or managing follicular lymphoma in a subject, comprising administering to the subject in need thereof a
therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0023] Provided herein is a method of treating, preventing, or managing transformed follicular lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0024] Provided herein is a method of treating, preventing, or managing mantle cell lymphoma in a subject, comprising administering to the subject in need thereof a
therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0025] Provided herein is a method of treating, preventing, or managing leukemia in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0026] Provided herein is a method of treating, preventing, or managing chronic lymphocytic leukemia in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0027] Provided herein is a method of treating, preventing, or managing Richter's transformation in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
[0028] Provided herein is a method of treating, preventing, or managing acute lymphoblastic leukemia in a subject, comprising administering to the subject in need thereof
a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed treatment with a CD19-directed CAR-T cell therapy.
DETAILED DESCRIPTION
[0029] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0030] Generally, the nomenclature used herein and the laboratory procedures in medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0031] The term "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 the disease, disorder or condition, or the symptom. When a disease, disorder or condition, or a symptom thereof, are being prevented, administration of the substance typically occurs before the onset of the disease, disorder or condition, or the symptom.
[0032] The term "subject" refers to an animal, including, but not limited to, a primate
(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
[0033] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disease, disorder, or condition, or one or more of the symptoms associated with the disease, disorder, or condition; or alleviating or eradicating the cause(s) of the disease, disorder, or condition itself.
[0034] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disease, disorder, or condition, and/or its attendant symptoms; barring a subject from acquiring a disease, disorder, or condition; or
reducing a subject' s risk of acquiring a disease, disorder, or condition.
[0035] The term "manage," "managing," or "management" refers to preventing or slowing the progression, spread or worsening of a disease, disorder or condition, or one or more symptoms thereof. The beneficial effects that a subject derives from a prophylactic or therapeutic agent may not result in a cure of the disease, disorder or condition.
[0036] The term "therapeutically effective amount" or "effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease, disorder, or condition being treated. The term "therapeutically effective amount" or
"effective amount" also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0037] The term "prophylactically effective amount" is meant to include the amount of a compound that, when administered, is sufficient to inhibit or reduce a symptom of the disease, disorder, or condition being treated, or to prevent recurrence of the disease, disorder, or condition being treated.
[0038] The term "therapy" refers to a 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 term "therapies" or "therapy" refers 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 a medical personnel.
[0039] 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%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0040] The term "cancer" or "cancerous" refers to or describes the physiological
condition in mammals that is typically characterized by unregulated cell growth.
[0041] The term "hematological cancer" refers to blood-borne cancer (e.g., multiple myeloma, lymphoma, and leukemia).
[0042] The practice of the embodiments provided herein employ 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.); Glover, ed. (1985) DNA Cloning, Volumes I and II; Gait, ed. (1984) Oligonucleotide Synthesis; Hames & Higgins, eds. (1984) Nucleic Acid Hybridization; Hames & Higgins, eds. (1984) Transcription and Translation; 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 Weir and Blackwell, eds. (1986) Handbook of Experimental Immunology, Volumes I-IV.
[0043] In one embodiment, provided herein is a method of treating, preventing, or managing a hematological cancer in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0044] In certain embodiments, the hematological cancer is myeloma, lymphoma, or leukemia.
[0045] In one embodiment, the hematological cancer is myeloma. In another embodiment, the hematological cancer is multiple myeloma (MM). In yet another embodiment, the hematological cancer is refractory MM. In still another embodiment, the hematological cancer is relapsed MM.
[0046] In one embodiment, the hematological cancer is leukemia. In another embodiment, the hematological cancer is acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), Richter's transformation, hairy cell leukemia, myelodysplasia, a myeloproliferative disorder, chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, or B-cell acute lymphoblastic
leukemia. In yet another embodiment, the hematological cancer is AML. In yet another embodiment, the hematological cancer is ALL. In yet another embodiment, the
hematological cancer is adult T-cell leukemia. In yet another embodiment, the hematological cancer is CLL. In yet another embodiment, the hematological cancer is Richter's
transformation. In yet another embodiment, the hematological cancer is hairy cell leukemia. In yet another embodiment, the hematological cancer is myelodysplasia. In yet another embodiment, the hematological cancer is a myeloproliferative disorder. In yet another embodiment, the hematological cancer is CML. In yet another embodiment, the
hematological cancer is MDS. In yet another embodiment, the hematological cancer is HTLV-1 leukemia. In yet another embodiment, the hematological cancer is mastocytosis. In still another embodiment, the hematological cancer is B-cell acute lymphoblastic leukemia.
[0047] In one embodiment, the leukemia is CLL, ALL, or Richter's transformation.
[0048] In one embodiment, the hematological cancer is lymphoma. In another embodiment, the hematological cancer is diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus- type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, transformed follicular lymphoma, small lymphocytic lymphoma, T- cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma, or ALK-positive large B-cell lymphoma. In yet another embodiment, the hematological cancer is DLBCL. In yet another embodiment, the hematological cancer is B- cell immunoblastic lymphoma. In yet another embodiment, the hematological cancer is small non-cleaved cell lymphoma. In yet another embodiment, the hematological cancer is HTLV- 1 leukemia/lymphoma. In yet another embodiment, the hematological cancer is adult T-cell lymphoma. In yet another embodiment, the hematological cancer is MCL. In yet another embodiment, the hematological cancer is HL. In yet another embodiment, the hematological cancer is NHL. In yet another embodiment, the hematological cancer is AIDS-related lymphoma. In yet another embodiment, the hematological cancer is follicular lymphoma. In yet another embodiment, the hematological cancer is transformed follicular lymphoma. In yet another embodiment, the hematological cancer is small lymphocytic lymphoma. In yet another embodiment, the hematological cancer is T-cell/histiocyte rich large B-cell
lymphoma. In yet another embodiment, the hematological cancer is transformed lymphoma. In yet another embodiment, the hematological cancer is primary mediastinal (thymic) large B-cell lymphoma. In yet another embodiment, the hematological cancer is splenic marginal zone lymphoma. In yet another embodiment, the hematological cancer is nodal marginal zone lymphoma. In still another embodiment, the hematological cancer is ALK-positive large B-cell lymphoma.
[0049] In one embodiment, the hematological cancer is non-Hodgkin lymphoma. In another embodiment, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, transformed follicular lymphoma, or mantle cell lymphoma.
[0050] In one embodiment, provided herein is a method of treating, preventing, or managing leukemia in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0051] In another embodiment, provided herein is a method of treating, preventing, or managing CLL in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0052] In yet another embodiment, provided herein is a method of treating, preventing, or managing Richter's transformation in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0053] In yet another embodiment, provided herein is a method of treating, preventing, or managing ALL in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0054] In yet another embodiment, provided herein is a method of treating, preventing, or managing lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein
the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0055] In yet another embodiment, provided herein is a method of treating, preventing, or managing non-Hodgkin lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0056] In yet another embodiment, provided herein is a method of treating, preventing, or managing diffuse large B-cell lymphoma in a subject, comprising
administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0057] In yet another embodiment, provided herein is a method of treating, preventing, or managing primary mediastinal B-cell lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0058] In yet another embodiment, provided herein is a method of treating, preventing, or managing follicular lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0059] In yet another embodiment, provided herein is a method of treating, preventing, or managing transformed follicular lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0060] In still another embodiment, provided herein is a method of treating, preventing, or managing mantle cell lymphoma in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed prior treatment with a CD19-directed CAR-T cell therapy.
[0061] In certain embodiments, the hematological cancer is refractory. In certain embodiments, the hematological cancer is relapsed. In certain embodiments, the
hematological cancer is metastatic. In certain embodiments, the hematological cancer is drug-resistant.
[0062] In one embodiment, the subject having the hematological cancer has failed prior treatment with JCAR014 therapy. In another embodiment, the subject having the hematological cancer has failed prior treatment with JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has failed prior treatment with axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has failed prior treatment with one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0063] In certain embodiments, the subject having the hematological cancer has disease progression during or following a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression during or following JCAR014 therapy. In another embodiment, the subject having the hematological cancer has disease progression during or following JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression during or following JCAR017 therapy. In yet another embodiment, the subject having the
hematological cancer has disease progression during or following tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression during or following axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease progression during or following one of CD19-directed CAR-T cell therapies disclosed in US 7,446, 190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0064] In certain embodiments, the subject having the hematological cancer has disease progression within 24 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 24
months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has disease progression within 24 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 24 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 24 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 24 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease progression within 24 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0065] In certain embodiments, the subject having the hematological cancer has disease progression within 18 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 18 months after JCAR014 therapy. In another embodiment, the subject having the
hematological cancer has disease progression within 18 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 18 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease progression within 18 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0066] In certain embodiments, the subject having the hematological cancer has disease progression within 12 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 12 months after JCAR014 therapy. In another embodiment, the subject having the
hematological cancer has disease progression within 12 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 12 months after JCAR017 therapy. In yet another embodiment, the subject having the
hematological cancer has disease progression within 12 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 12 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease progression within 12 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0067] In certain embodiments, the subject having the hematological cancer has disease progression within 8 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 8 months after JCAR014 therapy. In another embodiment, the subject having the
hematological cancer has disease progression within 8 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 8 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 8 months after tisagenlecleucel
(CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 8 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease
progression within 8 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0068] In certain embodiments, the subject having the hematological cancer has disease progression within 6 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has disease progression within 6 months after JCAR014 therapy. In another embodiment, the subject having the
hematological cancer has disease progression within 6 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 6 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 6 months after tisagenlecleucel
(CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has disease progression within 6 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has disease
progression within 6 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0069] In certain embodiments, the subject having the hematological cancer has a relapse during or following a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse during or following JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse during or following JCAR015 therapy. In yet another embodiment, the subject having the
hematological cancer has a relapse during or following JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse during or following tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse during or following axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has a relapse during or following one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0070] In certain embodiments, the subject having the hematological cancer has a relapse within 24 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 24 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 24 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 24 months after axicabtagene ciloleucel (KTE- C19) therapy. In still another embodiment, the subject having the hematological cancer has a relapse within 24 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0071] In certain embodiments, the subject having the hematological cancer has a relapse within 18 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR014
therapy. In another embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 18 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 18 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 18 months after axicabtagene ciloleucel (KTE- C19) therapy. In still another embodiment, the subject having the hematological cancer has a relapse within 18 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0072] In certain embodiments, the subject having the hematological cancer has a relapse within 12 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 12 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 12 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 12 months after axicabtagene ciloleucel (KTE- C19) therapy. In still another embodiment, the subject having the hematological cancer has a relapse within 12 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0073] In certain embodiments, the subject having the hematological cancer has a relapse within 8 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 8 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 8 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 8 months after axicabtagene ciloleucel (KTE-C19)
therapy. In still another embodiment, the subject having the hematological cancer has a relapse within 8 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0074] In certain embodiments, the subject having the hematological cancer has a relapse within 6 months after a CD19-directed CAR-T cell therapy. In one embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR014 therapy. In another embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR015 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 6 months after JCAR017 therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 6 months after tisagenlecleucel (CTL019) therapy. In yet another embodiment, the subject having the hematological cancer has a relapse within 6 months after axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment, the subject having the hematological cancer has a relapse within 6 months after one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0075] In certain embodiments, the hematological cancer is refractory to a CD 19- directed CAR-T cell therapy. In one embodiment, the hematological cancer is refractory to JCAR014 therapy. In another embodiment, the hematological cancer is refractory to
JCAR015 therapy. In yet another embodiment, the hematological cancer is refractory to JCAR017 therapy. In yet another embodiment, the hematological cancer is refractory to tisagenlecleucel (CTL019) therapy. In yet another embodiment, the hematological cancer is refractory to axicabtagene ciloleucel (KTE-C19) therapy. In still another embodiment the hematological cancer is refractory to one of CD19-directed CAR-T cell therapies disclosed in US 7,446,190 B2 and US 9,855,298 B2, the disclosure of each of which is incorporated herein by reference in its entirety.
[0076] In certain embodiments, the therapeutically effective amount is ranging from about 1 mg/kg every four weeks to about 50 mg/kg every week. In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every four weeks. In certain embodiments, the therapeutically effective amount is ranging from about 5 to about 25 mg/kg every four weeks. In certain embodiments, the therapeutically effective amount is
about 5, about 10, about 15, about 20, or about 25 mg/kg every four weeks.
[0077] In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every three weeks. In certain embodiments, the therapeutically effective amount is ranging from about 5 to about 25 mg/kg every three weeks. In certain embodiments, the therapeutically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every three weeks.
[0078] In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every two weeks. In certain embodiments, the therapeutically effective amount is ranging from about 2 to about 20 mg/kg every two weeks. In certain embodiments, the therapeutically effective amount is about 2, about 5, about 10, about 15, or about 20 mg/kg every two weeks.
[0079] In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 50 mg/kg every week. In certain embodiments, the therapeutically effective amount is ranging from about 1 to about 20 mg/kg every week. In certain embodiments, the therapeutically effective amount is about 1, about 2, about 5, about 10, about 15, or about 20 mg/kg every week.
[0080] In certain embodiments, the therapeutically effective amount is ranging from about 100 mg every four weeks to about 5,000 mg every week. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 5,000 mg every four weeks. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 2,500 mg every four weeks. In certain embodiments, the therapeutically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every four weeks.
[0081] In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 5,000 mg every three weeks. In certain embodiments, the therapeutically effective amount is ranging from about 500 to about 2,500 mg every three weeks. In certain embodiments, the therapeutically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every three weeks.
[0082] In certain embodiments, the therapeutically effective amount is ranging from
about 200 to about 5,000 mg every two weeks. In certain embodiments, the therapeutically effective amount is ranging from about 200 to about 2,000 mg every two weeks. In certain embodiments, the therapeutically effective amount is about 200, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg every two weeks.
[0083] In certain embodiments, the therapeutically effective amount is ranging from about 100 to about 5,000 mg every week. In certain embodiments, the therapeutically effective amount is ranging from about 100 to about 1,000 mg every week. In certain embodiments, the therapeutically effective amount is about 100, about 200, about 500, about 750, or about 1,000 mg every week.
[0084] In certain embodiments, the prophylactically effective amount is ranging from about 1 mg/kg every four weeks to about 50 mg/kg every week. In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every four weeks. In certain embodiments, the prophylactically effective amount is ranging from about 5 to about 25 mg/kg every four weeks. In certain embodiments, the prophylactically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every four weeks.
[0085] In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every three weeks. In certain embodiments, the prophylactically effective amount is ranging from about 5 to about 25 mg/kg every three weeks. In certain embodiments, the prophylactically effective amount is about 5, about 10, about 15, about 20, or about 25 mg/kg every three weeks.
[0086] In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every two weeks. In certain embodiments, the prophylactically effective amount is ranging from about 2 to about 20 mg/kg every two weeks. In certain embodiments, the prophylactically effective amount is about 2, about 5, about 10, about 15, or about 20 mg/kg every two weeks.
[0087] In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 50 mg/kg every week. In certain embodiments, the prophylactically effective amount is ranging from about 1 to about 20 mg/kg every week. In certain embodiments, the prophylactically effective amount is about 1, about 2, about 5, about 10, about 15, or about 20 mg/kg every week.
[0088] In certain embodiments, the prophylactically effective amount is ranging from about 100 mg every four weeks to about 5,000 mg every week. In certain embodiments, the prophylactically effective amount is ranging from about 500 to about 5,000 mg every four weeks. In certain embodiments, the prophylactically effective amount is ranging from about 500 to about 2,500 mg every four weeks. In certain embodiments, the prophylactically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every four weeks.
[0089] In certain embodiments, the prophylactically effective amount is ranging from about 500 to about 5,000 mg every three weeks. In certain embodiments, the
prophylactically effective amount is ranging from about 500 to about 2,500 mg every three weeks. In certain embodiments, the prophylactically effective amount is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every three weeks.
[0090] In certain embodiments, the prophylactically effective amount is ranging from about 200 to about 5,000 mg every two weeks. In certain embodiments, the prophylactically effective amount is ranging from about 200 to about 2,000 mg every two weeks. In certain embodiments, the prophylactically effective amount is about 200, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg every two weeks.
[0091] In certain embodiments, the prophylactically effective amount is ranging from about 100 to about 5,000 mg every week. In certain embodiments, the prophylactically effective amount is ranging from about 100 to about 1,000 mg every week. In certain embodiments, the prophylactically effective amount is about 100, about 200, about 500, about 750, or about 1,000 mg every week.
[0092] In certain embodiments, durvalumab is administered cyclically. In certain embodiments, durvalumab is administered in a 28-day cycle. In certain embodiments, durvalumab is administered twice in a 28-day cycle. In certain embodiments, durvalumab is administered every two weeks in a 28-day cycle. In certain embodiments, durvalumab is administered on days 1 and 15 in a 28-day cycle. In certain embodiments, durvalumab is administered once in a 28-day cycle. In certain embodiments, durvalumab is administered once on day 1 in a 28-day cycle. In certain embodiments, durvalumab is administered once on day 15 in a 28-day cycle.
[0093] In certain embodiments, durvalumab is administered twice in 28 days, followed by once every 28 days. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days, followed by once every 28 days. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days in an amount of about 10 mg/kg, followed by once every 28 days in an amount of about 20 mg/kg. In certain embodiments, durvalumab is administered on days 1 and 15 in 28 days in an amount of about 0.75 g, followed by once every 28 days in an amount of about 1.5 g.
[0094] In certain embodiments, durvalumab is administered parenterally. In certain embodiments, durvalumab is administered intravenously. In certain embodiments, durvalumab is administered via an intravenous infusion. In certain embodiments, durvalumab is administered via an intravenous infusion over 60 minutes.
[0095] The methods provided herein encompass treating a subject regardless of subject's age, although some diseases or disorders are more common in certain age groups.
[0096] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
[0097] Durvalumab can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a disease, disorder, or condition described herein.
[0098] As used herein, the term "in combination" includes the use of more than one therapy {e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies {e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy {e.g., a prophylactic or therapeutic agent such as durvalumab) can be administered prior to {e.g., 6 minutes, 16 minutes, 30 minutes, 46 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48 hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 7 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to {e.g., 6 minutes, 16 minutes, 30 minutes, 46 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48 hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 7 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy {e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.
[0099] The route of administration of durvalumab is independent of the route of administration of a second therapy. The second therapy 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.
[00100] In certain embodiments, each method provided herein may independently, further comprise the step of administering a second therapeutic agent {i.e., a second therapy).
[00101] Examples of second therapeutic agents include, but are not limited to:
ABRAXANE®; ace-11; acivicin; aclambicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;
calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride;
carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane;
mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin;
oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;
perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; pomalidomide; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; romidepsin; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; stem cell treatments such as PDA-001;
streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thalidomide; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;
vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
[00102] Additional examples of second therapeutic agents include, but are not limited to: 0-epi-l,25 dihy droxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix;
anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
calcipotriol; calphostin C; camptothecin derivatives; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;
dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;
fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin;
hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., GLEEVEC®), imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate;
lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;
maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin;
monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline;
N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (GENASENSE®); 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel
analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors;
purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl;
safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;
senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors;
sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;
thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[00103] In certain embodiments, the active agents of a combination therapy provided herein are administered cyclically to the subject. A cycling therapy involves the
administration of active agents for a period of time, followed by a rest for a period of time, and repeating this sequential administration. A 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.
[00104] The disclosure will be further understood by the following non-limiting examples.
EXAMPLES
[00105] As used herein, the symbols and conventions used in these processes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry.
Example 1
Efficacy And Safety Study Of Durvalumab In Subjects With NHL, CLL, or ALL Who Have Failed Prior Treatment With CD19-directed Chimeric Antigen Receptor T Cells
[00106] A phase 2, multicenter, single-arm, open-label study is conducted to evaluate the efficacy and safety of durvalumab in subjects with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL) who have failed (progressed, relapsed, or have not responded to) prior treatment with CD19-directed chimeric antigen receptor (CAR) T cells.
[00107] A primary outcome measure for NHL is an overall response rate in NHL subjects who have failed prior treatment with JCAR017. The number of subjects with best disease response of complete response (CR) or partial response (PR) during durvalumab treatment is determined according to the International Working Group (IWG) Response Criteria for Malignant Lymphoma (the Lugano Classification) or the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Response Criteria.
[00108] A secondary outcome measure for the NHL subjects who have failed prior treatment with JCAR017 is a complete response rate (CRR). The percentage of the NHL subjects achieved CR following durvalumabe administration is determined.
[00109] A primary outcome measure for NHL is an overall response rate in NHL subjects who have failed prior treatment with a CD-19-directed CAR T cell therapy other
than JCAR017. The percentage of subjects with best disease response of complete response (CR) or partial response (PR) during durvalumab treatment is determined according to the IWG Response Criteria for Malignant Lymphoma (the Lugano Classification) or the IWCLL Response Criteria.
[00110] A secondary outcome measure for the NHL subjects who have failed prior treatment with a CD-19-directed CAR T cell therapy other than JCAR017is a CRR. The percentage of NHL subjects achieved CR following durvalumabe administration is determined.
[00111] A primary outcome measure for CLL is an overall response rate in CLL subjects who have failed prior treatment with JCAR017. The percentage of subjects with best disease response of CR, complete response with incomplete bone receovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL) is determined.
[00112] A secondary outcome measure for CLL is a CRR. The percentage of CLL subjects achieved CR following durvalumabe administration is determined.
[00113] A primary outcome measure for ALL is an overall response rate in ALL subjects who have failed prior treatment with JCAR017. The percentage of subjects with best disease response of CR or CRi is determined.
[00114] A secondary outcome measure for ALL is a CRR. The percentage of ALL subjects achieved CR following durvalumabe administration is determined.
[00115] Percentages of subjects achieving a CR/CRi and/or minimal residual disease (MRD) negativity as well as duration of response (DoR), progression-free survival (PFS), and overall survival (OS) for patients with NHL, CLL, and ALL are determined. The percentage of CLL subjects achieving MRD negativity following durvalumab administration is determined. The percentage of ALL subjects achieving MRD negativity following durvalumab administration is determined.
[00116] Duration of response (i.e., the time from first CR or PR to progressive disease
(PD) or death) is determined for NHL subjects. Duration of response (i.e., the time from first CR, CRi, nPR, PR, or PRL to PD or death) is determined for CLL subjects. Duration of
response (i.e., the time from first CR or CRi to PD or death) is determined for ALL subjects.
[00117] Progression-free survival (i.e., the time from first durvalumab infusion to the first documentation of progressive disease, disease relapse, or death, whichever occurs first) is determined. Overall survival (i.e., the time from the furvalumab infusion to time of death due to any cause) is determined.
[00118] The study enrolls approximately 88 subjects (> 18 years of age), including three cohorts of subjects, separated by disease type, who have failed prior treatment with JCAR017. In Cohort 1 (post JCAR017), the subjects have NHL, including diffuse large B- cell lymphoa (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), transformed FL (tFL), and mantle cell lymphoma (MCL). In Cohort 2 (post JCAR017), the subjects have CLL or Richter's transformation. In Cohort 3 (post JCAR017), the subjects have ALL.
[00119] In addition to the three cohorts with subjects who have failed prior treatment with JCAR017, subjects in Cohort 4 are those, irrespective of disease type, who have failed prior treatment with a CD19-directed CAR T cell therapy. The subjects in Cohort 4 (post other CD19-directed CAR T cells) are those with NHL, including DLBCL, PMBCL, FL, tFL, or MCL after any previous CD19-directed CAR T cells treatment other than JCAR017.
[00120] The subjects in the study have progressive disease after the most recent therapy with JCAR017 or other anti CD- 19 directed chimeric antigen receptor T cells, or relapse to the most recent therapy with JCAR017 or other anti CD- 19 directed chimeric antigen receptor T cells. In vivo expansion of CAR T cells after infusion is mandatory. PD or relapse is defined according to: (i) the TvVG Response Criteria for Malignant Lymphoma (the Lugano Classification) for NHL; (ii) the TvVCLL Response Criteria for CLL; and (iii) National Comprehensive Cancer Network (NCCN) guidelines for ALL.
[00121] The subjects in the study meet criteria for needed treatment according to the European Socieity for Medical Oncology (ESMO) Clinical Practice Guidelines, National Comprehensive Cancer Network. The subject in the study have a Eastern Cooperative Onlogy Group (ECOG) performance-status core of 2 or less. Also toxicities resulting from CD19-directed CAR T cell therapy (including cytokine release syndrome (CRS) and/or nuerotoxi cities) must have resolved or stabilized to < Grade 1.
[00122] Each treatment cycle consists of 28 days. Subjects receive durvalumab at a dose of 750 mg on Days 1 and 15 of Cycle 1, followed by a dose of 1,500 mg once every four weeks (Q4 weeks or Q4wk) for up to 12 additional cycles.
[00123] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein.
Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.
Claims
1. A method of treating, preventing, or managing a hematological cancer in a subject, comprising administering to the subject in need thereof a therapeutically or prophylactically effective amount of durvalumab, wherein the subject has failed a CD 19- directed CAR-T cell therapy.
2. The method of claim 1, wherein the subject has disease progression during or following a CD19-directed CAR-T cell therapy.
3. The method of claim 2, wherein the subject has disease progression within 24 months after a CD19-directed CAR-T cell therapy.
4. The method of claim 2, wherein the subject has disease progression within 18 months after a CD19-directed CAR-T cell therapy.
5. The method of claim 2, wherein the subject has disease progression within 12 months after a CD19-directed CAR-T cell therapy.
6. The method of claim 2, wherein the subject has disease progression within 8 months after a CD19-directed CAR-T cell therapy.
7. The method of claim 2, wherein the subject has disease progression within 6 months after a CD19-directed CAR-T cell therapy.
8. The method of claim 1, wherein the subject has a relapse during or following a CD19-directed CAR-T cell therapy.
9. The method of claim 8, wherein the subject has a relapse within 24 months after a CD19-directed CAR-T cell therapy.
10. The method of claim 8, wherein the subject has a relapse within 18 months after a CD19-directed CAR-T cell therapy.
11. The method of claim 8, wherein the subject has a relapse within 12 months after a CD19-directed CAR-T cell therapy.
12. The method of claim 8, wherein the subject has a relapse within 8 months after a CD19-directed CAR-T cell therapy.
13. The method of claim 8, wherein the subject has a relapse within 6 months after a CD19-directed CAR-T cell therapy.
14. The method of any one of claims 1 to 13, wherein the hematological cancer is refractory to a CD19-directed CAR-T cell therapy.
15. The method of any one of claims 1 to 14, wherein the hematological cancer is a lymphoma.
16. The method of claim 15, wherein the hematological cancer is non-Hodgkin lymphoma.
17. The method of claim 16, wherein the hematological cancer is diffuse large B- cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma, transformed follicular lymphoma, or mantle cell lymphoma.
18. The method of claim 17, wherein the hematological cancer is diffuse large B- cell lymphoma.
19. The method of claim 17, wherein the hematological cancer is primary mediastinal B-cell lymphoma.
20. The method of claim 17, wherein the hematological cancer is follicular lymphoma.
21. The method of claim 17, wherein the hematological cancer is transformed follicular lymphoma.
22. The method of claim 17, wherein the hematological cancer is mantle cell lymphoma.
23. The method of any one of claims 1 to 14, wherein the hematological cancer is leukemia.
24. The method of claim 23, wherein the hematological cancer is chronic lymphocytic leukemia or Richter's transformation.
25. The method of claim 23, wherein the hematological cancer is chronic lymphocytic leukemia.
26. The method of claim 23, wherein the hematological cancer is Richter's transformation.
27. The method of claim 23, wherein the hematological cancer is acute
lymphoblastic leukemia.
28. The method of any one of claims 1 to 27, wherein the CD19-directed CAR-T cell therapy is JCAR014 therapy.
29. The method of any one of claims 1 to 27, wherein the CD19-directed CAR-T cell therapy is JCAR015 therapy.
30. The method of any one of claims 1 to 27, wherein the CD19-directed CAR-T cell therapy is JCAR017 therapy.
31. The method of any one of claims 1 to 27, wherein the CD19-directed CAR-T cell therapy is tisagenlecleucel therapy.
32. The method of any one of claims 1 to 27, wherein the CD19-directed CAR-T cell therapy is axicabtagene ciloleucel therapy.
33. The method of any one of claims 1 to 32, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 1 mg/kg every four weeks to about 50 mg/kg every week.
34. The method of claim 33, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 1 to about 50 mg/kg every two weeks.
35. The method of claim 34, wherein the therapeutically or prophylactically effective amount of durvalumab is about 2, about 5, about 10, about 15, or about 20 mg/kg every two weeks.
36. The method of claim 33, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 1 to about 50 mg/kg every four weeks.
37. The method of claim 36, wherein the therapeutically or prophylactically effective amount of durvalumab is about 5, about 10, about 15, about 20, or about 25 mg/kg every four weeks.
38. The method of any one of claims 1 to 32, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 100 mg every four weeks to about 5,000 mg every week.
39. The method of claim 38, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 200 to about 5,000 mg every two weeks.
40. The method of claim 38, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 200 to about 2,000 mg every two weeks.
41. The method of claims 38, wherein the therapeutically or prophylactically effective amount of durvalumab is about 200, about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, or about 2,000 mg every two weeks.
42. The method of claim 38, wherein the therapeutically or prophylactically effective amount of durvalumab is ranging from about 500 to about 5,000 mg every four weeks.
43. The method of claim 38, wherein the therapeutically or prophylactically effective amount of durvalumab is about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, or about 2,500 mg every four weeks.
44. The method of any one of claims 1 to 43, wherein durvalumab is administered cyclically.
45. The method of claim 44, wherein durvalumab is administered twice in a 28- day cycle.
46. The method of claim 45, wherein durvalumab is administered on days 1 and 15 in a 28-day cycle.
47. The method of claim 44, wherein durvalumab is administered once in a 28-day cycle.
48. The method of any one of claims 1 to 44, wherein durvalumab is administered twice in 28 days, followed by once every 28 days.
49. The method of claim 48, wherein durvalumab is administered on days 1 and 15 in 28 days, followed by once every 28 days.
50. The method of claim 48, wherein durvalumab is administered on days 1 and 15 in 28 days in an amount of about 10 mg/kg, followed by once every 28 days in an amount of about 20 mg/kg.
51. The method of claim 48, wherein durvalumab is administered on days 1 and 15 in 28 days in an amount of about 0.75 g, followed by once every 28 days in an amount of about 1.5 g.
52. The method of any one of claims 1 to 51, wherein durvalumab is administered parenterally.
53. The method of claim 52, wherein durvalumab is administered intravenously.
54. The method of any one of claims 1 to 53, wherein the subject is a human.
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US201762462265P | 2017-02-22 | 2017-02-22 | |
US62/462,265 | 2017-02-22 |
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Non-Patent Citations (3)
Title |
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CHONG ET AL.: "PD-1 blockade modulates chimeric antigen receptor (CAR).modified T cells: refueling the CAR", BLOOD, vol. 129, no. 8, 28 December 2016 (2016-12-28), pages 1039 - 1041, XP055535293 * |
HAMANISHI ET AL.: "PD-1/PD-L1 blockade in cancer treatment: perspectives and issues", INT J CLIN ONCOL, vol. 21, no. 3, June 2016 (2016-06-01), pages 462 - 473, XP055535295 * |
RUELLA ET AL.: "Catch me if you can: Leukemia Escape after CD 19-Directed T Cell Immunotherapies", COMPUT STRUCT BIOTECHNOL J., vol. 14, 28 September 2016 (2016-09-28), pages 357 - 362, XP055535300 * |
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