WO2022032132A1 - Advantageous therapies for disorders mediated by ikaros or aiolos - Google Patents
Advantageous therapies for disorders mediated by ikaros or aiolos Download PDFInfo
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- WO2022032132A1 WO2022032132A1 PCT/US2021/045000 US2021045000W WO2022032132A1 WO 2022032132 A1 WO2022032132 A1 WO 2022032132A1 US 2021045000 W US2021045000 W US 2021045000W WO 2022032132 A1 WO2022032132 A1 WO 2022032132A1
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- A61K31/499—Spiro-condensed pyrazines or piperazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Definitions
- the invention provides therapeutic compositions, combinations, and uses thereof to treat disorders mediated by transcriptional proteins Ikaros (IKZF1) and/or Aiolos (IKZF3) via degradation of these proteins through the ubiquitin proteasome pathway.
- IKZF1 transcriptional proteins Ikaros
- IKZF3 Aiolos
- the Ikaros family is a series of zinc-finger protein transcription factors that are important for certain physiological processes, particularly hematopoietic cells, and lymphocyte development (see Fan, Y. and Lu, D. “The Ikaros family of zinc-finger proteins” Acta Pharmaceutica Sinica B, 2016, 6:513-521). Ikaros (IKZF1) was first discovered in 1992 (see Georgopoulos, K. et al.
- Ikaros an early lymphoid-specific transcription factor and a putative mediator for T cell commitment” Science, 1992, 258:802-812), and over the subsequent two decades four additional homologs have been identified: Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5) (see John, L. B., and Ward, A.C. “The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity” Mol Immunol, 2011, 48: 1272-1278). The distribution of various members of the Ikaros protein family within the body varies significantly.
- Ikaros, Helios, and Aiolos are primarily found in lymphoid cells and their corresponding progenitors, with Ikaros additionally detected in the brain, and Ikaros and Helios detected in erythroid cells.
- Eos and Pegasus are more wide spread, and found in skeletal muscle, the liver, the brain, and the heart (see Perdomo, J. et al. “Eos and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities: J Biol Chem, 2000, 275:38347-38354; Schmitt, C. et al.
- Ikaros is important for proper lymphocyte development. Deletion of the exons encoding the first three N-terminal zinc fingers leads to mice lacking T-cells, B-cells, natural killer (NK) cells, and their progenitors. Genetic alterations in Ikaros are correlated with a poor outcome in the treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells and lymphoma cells.
- ALL acute lymphoblastic leukemia
- MM Multiple myeloma
- MM is a plasma cell malignancy typically characterized by the abnormal production of monoclonal immunoglobulin, bone marrow involvement, renal dysfunction, immune dysfunction, and skeletal damage.
- MM represents nearly 1.8% of all new cancers.
- outcomes for subjects with MM have improved substantially over the past several decades, the disease remains incurable with a predicted five- year relative survival rate currently of 53.9%.
- therapies are not curative, almost all patients ultimately progress.
- MM historically included chemotherapy, including alkylating agents together with corticosteroids. Treatment was further advanced in the 1980’ s with autologous stem cell transplants. In the 1990's the discovery of thalidomide (first-in-class immunomodulatory imide drug, IMiD®) efficacy in myeloma led to large shifts in treatment regimens and improvements in patient outcomes. The follow-on approved IMiD®s, lenalidomide and pomalidomide, are now widely used to treat MM, as is the first-in-class agent thalidomide.
- IMiD® first-in-class immunomodulatory imide drug
- This class of agents binds the E3 ligase substrate-recognition adapter protein cereblon (CRBN) and promote the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in antitumor effects, effects on the tumor microenvironment and immune modulation resulting in T-cell priming and antitumor activity.
- CRBN E3 ligase substrate-recognition adapter protein cereblon
- IKZF1 Ikaros
- IKZF3 Aiolos
- Many patients with MM are treated with multiple regimens containing one of these IMiDs.
- These drugs are now considered standard of care for the treatment of MM in numerous lines of therapy, in combination with agents including dexamethasone, anti-cluster of differentiation 38 (CD38) antibodies, and proteasome inhibitors, such as bortezomib.
- Non-Hodgkin’s Lymphoma is a heterogenous group of lymphoid malignancies originating from T, B or NK cells. It includes diffuse large B-cell lymphoma, anaplastic large-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, follicular lymphoma, cutaneous T-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, MALT lymphoma, and small-cell lymphocytic lymphoma. B-cell NHL predominates, while T-cell lymphomas are less common.
- rituximab in combination with CHOP is the main therapy administered to new diagnosed patients.
- initial chemotherapy is followed by autologous stem cell rescue.
- various targeted agents have been developed, thus improving treatment options in multiple subtypes of NHL, however these treatment options tend not to be curative.
- the NHL subtypes are biologically heterogeneous limiting the development of therapeutic agents broadly across indications.
- NHL Bruton Tyrosine Kinase
- MCL mantle cell lymphoma
- CAR-T chimeric antigen receptors T-cell
- DBLCL diffuse large B-cell lymphoma
- Drugs recently approved for T-cell NHL include romidepsin, belinostat, and brentuximab.
- lenalidomide has demonstrated clinical activity in both B-cell and T-cell NHL, including MCL, DLBCL and peripheral T-cell lymphoma (PTCL).
- Lenalidomide was studied in the relapsed/refractory (r/r) MCL population and was approved by the Food and Drug Administration (FDA) in June 2013 following results from the Phase II EMERGE study which examined the efficacy and safety of lenalidomide in r/r subjects with MCL following bortezomib (overall response rate [ORR] 28%; median duration of response [DOR] 16.6 months).
- FDA Food and Drug Administration
- Protein degradation is a highly regulated and essential process that maintains cellular homeostasis.
- the selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP).
- UPP ubiquitin-proteasome pathway
- the UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection.
- Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins.
- Defective proteasomal degradation has been linked to a variety of clinical disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophies, cardiovascular disease, and cancer among others.
- Patent applications that describe certain protein degraders include WO 2020/210630, WO 2020/006262, WO 2020/010227, and WO 2020/010177.
- Patent applications filed by C4 Therapeutics, Inc. that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO/2021/127561 titled “Isoindolinone And Indazole Compounds For The Degradation Of EGFR”; WO/2021/086785 titled “Bifunctional Compounds”; WO/2021/083949 titled “Bifunctional Compounds for the Treatment of Cancer”; WO/2020/210630 titled “Tricyclic Degraders of Ikaros and Aiolos”; WO/2020/181232 titled “Heterocyclic Compounds for Medical Treatment”; WO/2020/132561 titled “Targeted Protein Degradation”; WO/2019/236483 titled “Spirocyclic Compounds”; W02020/051235 titled “Compounds for the degradation of BRD9 or MTH1”; WO/2019/191112 titled “Cereblon binders for the Degrad
- Compound 1 is a small molecule anti-cancer agent that binds with high affinity to the cereblon E3 ligase thereby creating a new surface on cereblon that interacts with IKZF 1 and IKZF3 (see WO 2020/210630).
- IKZF1 and IKZF3 are efficiently ubiquitinated by the cereblon E3 ligase and degraded by the proteasome.
- the high cereblon binding affinity of Compound 1 enables rapid, deep, and durable degradation of IKZF 1/3 resulting in potent activity in cancer cells, for example including but not limited to, hematopoietic cancers such as multiple myeloma and the multiple types of Non-Hodgkin’s Lymphoma.
- Compound 1, and other compounds described herein can be administered to treat disorders mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) in a low dosage regimen once or twice a day, optionally with a drug holiday, in highly effective treatment regimens.
- anti-cancer treatment can be effective for a patient using one of the compounds described herein with a dosage of not more than about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125 or even 100, 75, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 micrograms ( ⁇ g) once a day (QD) or twice a day (BID).
- the patient is an adult (typically a human of at least 100 pounds or more, and sometimes even 125 or 150 pounds (e.g., 70 kg or more and at least typically 18 years old or more).
- the patient is pediatric (and may be less than 100, 125 or 150 pounds and typically less than 18 years old).
- Compound 1 is effective as a low dose therapy, but it can also be delivered with a drug holiday which is advantageous to the patient.
- Compound 1 can be delivered once or twice a day for 21 days followed by a drug holiday of 7 days.
- Alternative dosing regimens are also useful, for example, including but not limited to those that increase or decrease the drug holiday by 1, 2, 3, 4, 5, 6, or 7 days.
- Compound 1 or another compound described herein modulates the patient’s immune activity.
- Compound 1 activates proliferation of cytotoxic T-cells, which can be critical to anti-cancer therapy.
- Compound 1 or another compound described herein in a non-limiting embodiment can be administered daily or intermittently with dexamethasone.
- dexamethasone or another corticosteroid or another immunosuppressant or anti-inflammatory agent is administered every day without a drug holiday for the 28-day cycle.
- the dexamethasone or another corticosteroid or another immunosuppressant or anti-inflammatory agent is administered with a drug holiday, which may be the same or different from that of Compound 1 or another compound described herein.
- the low dose Ikaros (IKZF1) and/or Aiolos (IKZF3) degrading compound is Compound 1 or a pharmaceutically acceptable salt thereof.
- the high binding affinity and degradation catalysis of Compound 1 enables potent cell growth inhibition in both previously untreated NCIH929 multiple myeloma cell lines (96% maximal growth inhibition, mean half maximal inhibitory concentration IC 50 of 0.071 nM) and NCIH929 cells made resistant to both lenalidomide and pomalidomide (70% maximal growth inhibition, mean IC 50 of 2.3 nM).
- the compounds described herein can be used to treat cancer cells that are resistant, refractive or unresponsive to standard of care therapies for cancers mediated by IKZF1 or IKZF3, including IMiDs including pomalidomide or any of those described in the Background or Detailed Description.
- Compound 1 has demonstrated strong anti-cancer activity in a panel of multiple myeloma cell lines (eight of twelve were responsive, mean IC 50 of 0.3 nM among responsive lines). Anti-cancer activity with Compound 1 was also demonstrated in several cell line models of various Non-Hodgkin’s Lymphoma subtypes, including mantel cell lymphoma (MCL) (four of six lines tested were responsive mean IC 50 of 13 nM among the responsive lines), diffuse large B-cell lymphoma (DLBCL) (six of eleven germinal center B-cell like DLBCL and three of six activated B-cell DLBCL lines were responsive, with mean IC 50 of 12 nM and 1.6 nM respectively, amongst the responsive lines), anaplastic large cell lymphoma (ALCL) (four out of six cell lines were responsive, mean IC 50 of 1.7 nM among the responsive lines) and cutaneous T- cell lymphoma (CTCL) (three of four cell lines tested were responsive, mean IC 50 of
- Compound 1 demonstrated dose dependent efficacy from 3 ⁇ g/kg/day to 100 ⁇ g/kg/day (see Example 13). In several tumor xenografts tested daily dosing of Compound 1 at dose of 30 ⁇ g/kg/day to 100 ⁇ g/kg/day led to durable tumor regression. As shown in Figure 45A, Figure 45B, Figure 45C, Figure 52, and others Compound 1 is more than 100-fold more potent than pomalidomide in a variety of cancer assays.
- Compound 1 has measurable plasma and tumor concentrations for longer than CC-92480 (currently in human clinical trials by Celgene, a subsidiary of Bristol Myers Squibb) despite being dosed at a 10-fold lower dose. It also takes significantly longer for IKZF3 levels to recover after treatment with Compound 1 than pomalidomide or CC-92480. For example, in an NCI-H929 tumor model it takes more than 48 hours for the IKZF3 level to reach 50% of its pretreatment level after administration of Compound 1, whereas both CC-92480 (at a x10 higher dose) and pomalidomide (at a x30 higher dose) reach pretreatment levels of IKZF3 within 48 hours of treatment.
- Ikaros (IKZF1) and/or Aiolos (IKZF3) new advantageous treatments of disorders mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) have been discovered.
- Ikaros (IKZF1) and/or Aiolos (IKZF3) degrading compounds described herein can be used, in non-limiting examples as follows:
- a dosage is not more than about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 micrograms ( ⁇ g) once a day (QD) or twice a day (BID), optionally with a drug holiday.
- QD a day
- BID twice a day
- IKZF1 Ikaros
- IKZF3 Aiolos
- a tumor immunity marker e.g., a cytokine, tumor infiltrating lymphocyte, T-cell activation and/or proliferation, or a B-cell marker such as BCMA or M-protein, or a combination thereof
- an apoptotic marker e.g., total and/or cleaved caspase- 1, caspase-3, caspase-7, PARP, BIM, or survivin, or a combination thereof
- a zinc finger protein e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof
- IKZF1 Ikaros
- IKZF3 Aiolos
- a blood or tissue sample is first taken from the patient and the concentration of one or more biomarkers, for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇ , is determined, and wherein if the patient has a statistically lower concentration of the biomarker than a healthy person, including but not limited to up to about 5, 10, 15 or 20% lower, then Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein is administered to the patient.
- biomarkers for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇
- IKZF1 and/or Aiolos IKZF3
- a blood or tissue sample is first taken from the patient and the concentration of one or more biomarkers, for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC is determined, and wherein if the patient has a statistically higher concentration of biomarker including but not limited to up to about 5, 10, 15 or 20% higher than a healthy person then Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein is administered to the patient.
- biomarkers for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC
- Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein is administered to the patient.
- IKZF1 Ikaros
- IKZF3 Aiolos
- concentration of one or more biomarkers for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇ , is determined, wherein if the concentration of the biomarker is not significantly increased, for example by at least about 1.25, 1.5, 1.75, or 2-fold, then the dose of the compound is increased.
- IKZF 1 Ikaros
- IKZF3 Aiolos
- the patient is administered Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein and then a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers, for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC is determined, wherein if the concentration of the biomarker is not significantly decreased, for example by about 1.25, 1.5, 1.75, or 2-fold, then the dose of the compound is increased.
- biomarkers for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC
- a tumor immunity marker e.g., a cytokine, tumor infiltrating lymphocyte, T-cell activation and/or proliferation, and B-cell markers such as BCMA or M-protein, or a combination thereof
- an apoptotic marker e.g., total and/or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM, or survivin, or a combination thereof
- a zinc finger protein e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof
- a dosage is not more than about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125 or even 100, 75, 50 or 25 micrograms ( ⁇ g) once a day (QD) or twice a day (BID), optionally with a drug holiday.
- a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound described herein is used in combination with a BTK inhibitor for example a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.
- a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib,
- a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound described herein is used in combination with a CD38 antibody for example a CD38 antibody selected from felzartamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- IKZF1 Ikaros
- IKZF3 Aiolos
- a proteasome inhibitor for example a proteasome inhibitor selected from bortezomib, carfilzomib, ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP- 18770, NEOSH101, TQB3602, and KZR-616.
- a proteasome inhibitor selected from bortezomib, carfilzomib, ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP- 18770, NEOSH101, TQB3602, and KZR-616.
- IKZF1 Ikaros
- IKZF3 Aiolos
- IKZF1 and/or Aiolos IKZF3
- an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay 10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, 1- Alaninechlamy docin, depudecin, panobinostat, ricolinostat, vorinostat, and CUDC-101.
- HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay 10603
- IKZF1 and/or Aiolos IKZF3
- a compound described herein is used in combination with another compound, for example a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.
- a treatment of cancer mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) comprising administering an effective amount of Compound 1 to activate proliferation of T-cells.
- a compound described herein can be administered at a lower dose than first generation IMiDs; can penetrate the blood brain barrier to treat a central nervous system (CNS) involved cancer, for example a CNS involved lymphoma; can treat a cancer that has relapsed or is refractory to a standard of care regimen, including a first generation IMiD treatment; and/or can provide a longer period of progression free survival to the patient than 1 st generation IMiDs, for example thalidomide, pomalidomide, and lenalidomide.
- CNS central nervous system
- 1 st generation IMiDs for example thalidomide, pomalidomide, and lenalidomide.
- a compound described herein is about 30, 40, 50, 60, 70, 80, 90, 100, 500, or even 1,000 times more potent in vivo than thalidomide, pomalidomide, lenalidomide, or CC-92480.
- a compound described herein causes durable degradation of IKZF1 and/or IKZF3 (e.g. IKZF1 and/or IKZF3 levels take 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or longer to return to pretreatment levels). This durable degradation is a result of high in vivo efficacy, metabolic stability, and/or selectivity.
- the compound used in the treatments described herein is selected from: or a pharmaceutically acceptable salt thereof.
- a compound described herein modulates immune system activity, for example activating IFN-alpha, IFN-beta, or IFN-gamma. By activating the immune system, the compound can more effectively treat cancer.
- This immunomodulatory activity increases the efficacy of a compound described herein with another anti-cancer agent such as daratumumab.
- the degradation of IKZF1 and IKZF3 from malignant B or T cells result in tumor cell death, and their depletion from the tumor microenvironment results in T-cell activation.
- the compound may for example be provided for oral, parenteral or topical delivery.
- the compound is provided in a solid, gel or liquid dosage form for oral delivery, or may be provided intravenously.
- the selected compound is provided as a softshell capsule or a solid dosage form tablet for oral administration.
- the dose strengths of the pharmaceutical composition is about 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 50 ⁇ g, 75 ⁇ g, 100 ⁇ g, 125 ⁇ g, 150 ⁇ g, 175 ⁇ g, 200 ⁇ g, 225 ⁇ g, 250 ⁇ g, 275 ⁇ g, 300 ⁇ g, 325 ⁇ g, 350 ⁇ g, 375 ⁇ g, 400 ⁇ g, 425 ⁇ g, 450 ⁇ g, 475 ⁇ g, 500 ⁇ g, 525 ⁇ g, 550 ⁇ g, 575 ⁇ g, 600 ⁇ g, 625 ⁇ g, 650 ⁇ g, 675 ⁇ g, 700 ⁇ g, 725 ⁇ g, 750 ⁇ g, 775 ⁇ g, or 800 ⁇ g, which may in one nonlimiting aspect be given once daily (QD) or twice a day (BID) on days 1-21 of a 28- day treatment cycle.
- QD
- the compound may for example be provided for oral or parenteral delivery.
- the compound is provided in a solid, gel or liquid dosage form for oral delivery, or may be provided intravenously.
- the selected compound is provided as a softshell capsule or tablet for oral administration.
- the dose strengths of the solid or gel dosage form is 25 ⁇ g, 50 ⁇ g, 100 ⁇ g, 200 ⁇ g, 300 ⁇ g or 400 ⁇ g, which may in one nonlimiting aspect be given once daily (QD) on days 1-21 of a 28-day cycle.
- the compound used in the treatments described herein is Compound 1 or a pharmaceutically acceptable salt thereof.
- any of the compounds described herein have at least one desired isotopic substitution of an atom, at an amount about the natural abundance of the isotope, i.e., enriched.
- the compound includes a deuterium or multiple deuterium atoms.
- FIG. 1A is a dose-response curve describing the effect of Compound 1 on H929 cell viability compared to pomalidomide as described in Example 9.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the % H929 cell viability after 96 hours.
- FIG. IB is a dose-response curve describing the effect of Compound 1 on IKZF1 degradation compared to pomalidomide as described in Example 9.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the % IKZF1 remaining after 1.5 hours.
- FIG. 2A is a scatter plot of data from tumor lysates analyzed by multiplexed quantitative proteomics in mice treated with Compound 1 for 4 hours.
- Tumor lysates were analyzed by multiplexed quantitative proteomics and fold changes in relative abundance comparing treatment with Compound 1 to that with DMSO control were depicted in a scatter plot.
- Log2 fold changes are shown in the x axis and negative Log 10 adjusted P values are shown on the y axis.
- the horizontal dashed line marks the statistical significance (P adjusted ⁇ 0.01) and the vertical line marks fold change > 2.
- IKZF1 and IKZF3 are the only significantly downregulated proteins with a fold change of 5.5 and 4.1, respectively.
- FIG. 2B is a scatter plot of data from tumor lysates analyzed by multiplexed quantitative proteomics in mice treated with Compound 1 for 24 hours.
- Tumor lysates were analyzed by multiplexed quantitative proteomics and fold changes in relative abundance comparing treatment with Compound 1 to that with DMSO control were depicted in a scatter plot.
- Log2 fold changes are shown in the x axis and negative LoglO adjusted P values are shown on the y axis.
- the horizontal dashed line marks the statistical significance (P adjusted ⁇ 0.01) and the vertical line marks fold change > 2.
- the experimental procedure is provided in Example 10.
- FIG. 3 is a dose-response curve describing the effect of Compound 1 with and without bortezomib (proteasome inhibitor) or MLN-4924 (neddylation inhibitor) on Ikaros degradation.
- Ki-JK cells were exposed to Compound 1 with and without bortezomib or MLN-4924 and the IKZF1 concentration was determined by flow cytometry at 1.5, 3, and 6 hours for Compound 1 and 6 hours for the combination of Compound 1 and bortezomib or MLN-4924.
- the x-axis is the concentration of Compound 1 alone or in combination with bortezomib or MLN-4924.
- the y-axis is the remaining concentration of IKZF 1-488 measured as a percent relative to DMSO.
- FIG. 4 is a graph of the effect of Compound 1 in mice bearing multiple myeloma NCI- 14929 cells as described in Example 13.
- Compound 1 was administered orally (PO) every day (QD) at four different concentrations (3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, and 100 ⁇ g/kg) and compared to pomalidomide.
- the x-axis is the time measured in days and the y-axis is NCI-H929 tumor volume measured in mm 3 .
- FIG. 5 is a graph of the effect of Compound 1 in mice bearing multiple myeloma RPML
- Compound 1 was administered orally (PO) every day (QD) at four different concentrations (3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, and 100 ⁇ g/kg) and compared to pomalidomide.
- the x-axis is the time measured in days and the y-axis is RPMI-8226 tumor volume measured in mm 3 .
- FIG. 6 are images comparing mice administered Compound 1 and vehicle. Mice were imaged using IVIS Lumina II as described in Example 14.
- FIG. 7 is a graph of the bioluminescence signal of mice administered Compound 1 orally (PO) every day (QD) or vehicle and imaged using IVIS Lumina II as described in Example 14.
- the x-axis is time measured in days and the y-axis is the MMIS-Luc systemic BLI (total bioluminescence signal) measured in photons/10 6 .
- FIG. 8 is a graph of the tumor volume of mice injected with NCI-H929 pomalidomide resistant cells and administered Compound 1 (100 ⁇ g/kg) or pomalidomide (3000 ⁇ g/kg) orally (PO) every day (QD) as described in Example 15.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 9 is a graph of the tumor volume of mice injected with refractory multiple myeloma cell line RPMI-8226.
- mice were injected with RPMI-8226 tumors and the tumors were allowed to grow to a volume of 109-158 mm 3 (28 days after implantation).
- Vehicle treated animals continued treatment until tumors reached a MTV (mean tumor volume) of 2211 mm 3 .
- Pomalidomide treated animals were crossed over onto Compound 1 (100 ⁇ g/kg/day) at day 17 for 21 additional days.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 10 is a graph of the tumor volume of mice injected with lymphoma RECI mantle cells and administered Compound 1 or pomalidomide as described in Example 16.
- Compound 1 was administered at four different concentrations (3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, or 100 ⁇ g/kg) and pomalidomide was administered at a dose of 3000 ⁇ g/kg. Both agents were administered orally (PO) every day (QD).
- PO orally
- QD QD
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 11 is a graph of the tumor volume of mice injected with lymphoma TMD8 DLBCL and administered Compound 1 (100 ⁇ g/kg) or pomalidomide (3000 ⁇ g/kg) orally (PO) every day (QD) as described in Example 16.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 11 is a graph of the tumor volume of mice injected with lymphoma TMD8 DLBCL and administered Compound 1 (100 ⁇ g/kg) or pomalidomide (3000 ⁇ g/kg) orally (PO) every day (QD) as described in Example 16.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 12 is a graph of the tumor volume of mice injected with KI-JK ALCL tumors and administered Compound 1 at either 30 ⁇ g/kg or 100 ⁇ g/kg PO QD (orally every day) or pomalidomide (3000 ⁇ g/kg, QD PO) or CC-92480 (1000 ⁇ g/kg, QD PO) as described in Example 17.
- the mice were dosed for 21 days.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 13 A is a bar graph of IKZF1 protein expression in mice injection with KI-JK ALCL tumors and administered Compound 1 or pomalidomide as described in Example 17. Mice were sacrificed and tumors harvested at 6 and 24 hours post single dose. The x-axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of IKZF1 protein compared to the vehicle control normalized to GAPDH.
- FIG. 13B is a bar graph of IRF4 protein expression in mice injection with KI-JK ALCL tumors and administered Compound 1 or pomalidomide as described in Example 17. Mice were sacrificed and tumors harvested at 6 and 24 hours post single dose. The x-axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of IRF4 protein compared to the vehicle control normalized to GAPDH.
- FIG. 14 is a graph of the tumor volume of mice injected with DL-40 ALCL tumors and administered Compound 1, pomalidomide, or CC-92480 as described in Example 18.
- Compound 1 was administered at three different concentrations (10 ⁇ g/kg, 30 ⁇ g/kg, or 100 ⁇ g/kg) orally (PO) every day (QD).
- Pomalidomide was administered at a dose of 3000 ⁇ g/kg orally every day.
- CC- 92480 was administered at a dose of 300 ⁇ g/kg orally every day.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 15A is a graph of IKZF1 protein expression in mice injected with DL-40 ALCL tumors and administered Compound 1 or pomalidomide as described in Example 18. Mice were sacrificed and tumors harvested at 1, 4, and 24 hours post single dose. The x-axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of IKZF1 protein compared to the vehicle control normalized to GAPDH.
- FIG. 15B is a western blot measuring the concentration of IKZF1 and IKZF3 in mice injected with DL-40 ALCL tumors and administered Compound 1 or pomalidomide as described in Example 18. The concentration was determined when mice were sacrificed at 1, 4, and 24 hours post single dose.
- DL-40 ALCL tumors FIG. 16 is a graph of the tumor volume of mice injected with DL-40 ALCL tumors and administered Compound 1 or pomalidomide as described in Example 19.
- Compound 1 was administered at five different concentrations (3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, 100 ⁇ g/kg, or 300 ⁇ g/kg) orally (PO) every day (QD).
- Pomalidomide was administered at a dose of 3000 ⁇ g/kg orally every day.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured 3 in mm .
- FIG. 17 is a graph of the tumor volume of mice injected with DL-40 ALCL tumors and administered Compound 1 as described in Example 19.
- Compound 1 was administered at three different concentrations (30 ⁇ g/kg, 100 ⁇ g/kg, or 300 ⁇ g/kg) orally (PO) every day (QD).
- the x- axis is the time measured in days and the y-axis is the body weight change measured in percent.
- FIG. 18 is a graph of the tumor volume of mice injected with KLJK ALCL tumors and administered Compound 1 (100 ⁇ g/kg orally (PO) every day (QD)) as described in Example 20.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 19 is a graph of IKZF1, IKZF3, IRF-4, caspase-3, and IRF-1 protein expression in mice injected with KLJK ALCL tumors and administered Compound 1 as described in Example
- the x-axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of protein compared to the vehicle control normalized to GAPDH.
- FIG. 20 is a graph comparing the effect of Compound 1, ibrutinib, and the combination of Compound 1 and ibrutinib on TMD8 tumor volume in mice as described in Example 13.
- Compound 1 was administered at a dose of 50 ⁇ g/kg orally every day and ibrutinib was administered at a dose of 12.5 mg/kg orally every day.
- the combination was dosed at each agent’s respective dose.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 21 is a graph of the percent survival of mice bearing TMD8 DLBCL administered Compound 1, ibrutinib, and the combination of Compound 1 and ibrutinib as described in Example
- Compound 1 was administered at a dose of 50 ⁇ g/kg orally every day and ibrutinib was administered at a dose of 12.5 mg/kg orally every day. The combination was dosed at each agent’s respective dose.
- the x-axis is days post-dose and the y-axis is the percent survival.
- FIG. 22 is a graph comparing the effect of Compound 1, dexamethasone, and the combination of Compound 1 and dexamethasone on RPML8226 multiple myeloma tumor volume in mice as described in Example 22.
- Dexamethasone was administered at a dose of 5 mg/kg intravenously (IV) every week (QW) and Compound 1 was administered at a dose of 10 ⁇ g/kg orally every day.
- Compound 1 was dosed in combination with dexamethasone at each agent’s respective dose levels and schedules.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 23 is a graph of the percent survival of mice bearing RPMI-8226 multiple myeloma tumors administered Compound 1, dexamethasone, and the combination of Compound 1 and dexamethasone as described in Example 22.
- Dexamethasone was administered at a dose of 5 mg/kg intravenously (IV) every week (QW) and Compound 1 was administered at a dose of 10 ⁇ g/kg orally every day.
- Compound 1 was dosed in combination with dexamethasone at each agent’s respective dose levels and schedules.
- the x-axis is days post-dose and the y-axis is the percent survival.
- FIG. 24 is a graph measuring the concentration of IKZF1 and IKZF3 in a monkey administered Compound 1. As described in Example 23, one monkey was administered Compound 1 and blood was collected at 0, 4, and 24 hours post-dose to determine the concentration of IKZF1 and IKZF3.
- the x-axis is the time post-dosing measured in hours and the y-axis is the mean fluorescent intensity of IKZF1 and IKZF3.
- FIG. 25A is a graph measuring the plasma concentration of Compound 1 or Compound 14 following the administration of Compound 1 (60 ⁇ g/kg or 100 ⁇ g/kg) PO to monkeys as described in Example 24.
- the x-axis is time measured in hours and the y-axis is plasma concentration measured in ng/mL.
- FIG. 25B is a graph measuring the plasma concentration of Compound 1 or Compound 14 following the administration of Compound 1 (30 mg/kg) PO to a rat as described in Example 24.
- the x-axis is time measured in hours and the y-axis is plasma concentration measured in ng/mL.
- FIG. 26A is a graph measuring the effect of Compound 1 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26B is a graph measuring the effect of Compound 2 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26C is a graph measuring the effect of Compound 3 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26D is a graph measuring the effect of Compound 4 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26E is a graph measuring the effect of Compound 5 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26F is a graph measuring the effect of Compound 6 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26G is a graph measuring the effect of Compound 7 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26H is a graph measuring the effect of Compound 8 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 261 is a graph measuring the effect of Compound 9 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x- axis is treatment length measured in days and the y-axis is H929 tumor volume measured in mm 3 .
- FIG. 26 J is a graph measuring the effect of Compound 10 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26K is a graph measuring the effect of Compound 11 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 26L is a graph measuring the effect of Compound 12 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with DL-40 ALCL tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured 3 in mm .
- FIG. 26M is a graph measuring the effect of Compound 13 (100 ⁇ g/kg, QD PO) compared to vehicle on tumor volume in mice injected with H929 tumors as described in Example 25.
- the x-axis is treatment length measured in days and the y-axis is H929 tumor volume measured in 3 mm .
- FIG. 27 is a graph demonstrating the in-vitro binding of Compound 1 to purified cereblon- DDB1 was measured via fluorescent polarization experiment.
- Compound 1 (circles) or reference compound (Pomalidomide) competes with Alexa-647 based fluorescence probe for binding to cereblon-DDBl.
- Probe displacement results in a decreased level of fluorescent polarization that is used to calculate the fraction of the bound probe using the signals from positive and negative controls. Error bars represent the standard deviation (SD).
- the fluorescent polarization experiment is described in Example 26.
- FIG. 28 is a dose-response curve describing the displacement of a cereblon binding tracer molecule by Compound 1 or pomalidomide in 293T cells expressing cereblon-NanoLuc fusion as described in Example 27.
- FIG. 29 is a dose-response curve describing the effect of Compound 1 on IKZF1 degradation compared to pomalidomide as described in Example 9.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the % IKZF1 remaining after treatment with Compound 1 or pomalidomide for 1 or 2 hours.
- FIG. 30 is a western blot showing Aiolos and Ikaros levels remaining in H929 cells after 4 hours treatment with Compound 1 or pomalidomide in dose response. The method for this experiment is described in Example 28.
- FIG. 31 is a dose-response curve describing the effect of Compound 1 on Caspase 3/7 activity in NCH4929 multiple myeloma cell line compared to pomalidomide after 72 hour treatment as described in Example 29.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the luminescence signal (RLU) measured following addition of Caspase 3/7 substrate reagents. The method for this experiment is described in Example 29.
- FIG. 32 is a plot showing the effect of Compound 1 on growth of eight multiple myeloma cell lines compared to pomalidomide as described in Example 30.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM that inhibited cellular growth at 96 hours by 50% (IC 50 ) and the y-axis is the cell line tested.
- FIG. 33 is a graph showing the in vivo efficacy of Compound 1 and pomalidomide in the treatment of female NOD SCID mice bearing NCI-H929 multiple myeloma xenograft tumors.
- Mice we treated with the vehicle control, a dose response (3, 10, 30 and 100 ⁇ g/kg/day) of Compound 1, or 3000 ⁇ g/kg/day of pomalidomide for 21 days. All compounds were administered orally (PO) on a daily basis (QD) After 21 days of dosing tumors were monitored for regrowth. Arrow indicates rechallenging with 30 ⁇ g/kg/day of Compound 1 starting on Day 40.
- the x-axis is the time measured in days and the y-axis is NCI-H929 tumor volume measured in mm 3 . This assay is described in Example 31.
- FIG. 34 is a graph of the bioluminescence signal of mice administered Compound 1 orally (PO) every day (QD) or vehicle and imaged using IVIS Lumina II as described in Example 14.
- the x-axis is time measured in days and the y-axis is the MMIS-Luc systemic BLI (total bioluminescence signal) measured in photons/106.
- FIG. 35 is in vivo efficacy of Compound 1 and pomalidomide in the treatment of female CB17 SCID mice bearing RPM-8226 multiple myeloma xenograft tumors. Mice were treated with the vehicle control, a dose (3, 10, 30 and 100 ⁇ g/kg/day) of Compound 1, or 3000 ⁇ g/kg/day of pomalidomide for 21 days. All compounds were administered orally (PO) on a daily basis (QD). Tumors are graphed individually and represented as the percent of their original volume, as shown on the y-axis.
- FIG. 35 is in vivo efficacy of Compound 1 and pomalidomide in the treatment of female CB17 SCID mice bearing RPM-8226 multiple myeloma xenograft tumors. Mice were treated with the vehicle control, a dose (3, 10, 30 and 100 ⁇ g/kg/day) of Compound 1, or 3000 ⁇ g/kg/day of pomalidomide for 21
- Example 36 is a graph of IKZF3 protein expression in mice injected with RPMI-8226 tumors and administered a dose response of Compound 1 as described in Example 32.
- the x-axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of protein compared to the vehicle control normalized to GAPDH.
- FIG. 37 is a graph of IKZF1, IKZF3 and IRF-4, tumor protein expression in mice injected with RPMI-8226 MM tumors and administered Compound 1 as described in Example 32.
- the x- axis is labeled with the time post dose that the animal was sacrificed and the y-axis is the percent of protein compared to the vehicle control normalized to GAPDH.
- FIG. 38 is a western blot evaluating the levels of cereblon, IKZF1, and IKZF3 levels in H929 cells that were untreated (parental), treated with DMSO (LTC; long term culture), lenalidomide, or pomalidomide for four months. Vinculin was used as a loading control. The western blot was conducted using the method described in Example 33.
- FIG. 39 describes the effect of Compound 1 on growth of IMiD-resistant NCIH929 multiple myeloma cells compared to pomalidomide as described in Example 34.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the % viability of IMiD- resistant NCIH929 cells after 96 hours relative to untreated cells.
- FIG. 40 is a graph of the tumor volume of mice injected with refractory multiple myeloma cell line RPMI-8226. Mice were dosed orally daily with the vehicle control, pomalidomide (3000 ⁇ g/kg/day) or Compound 1 (100 ⁇ g/kg/day) for 35 days, with the exception of the pomalidomide group. For this group pomalidomide dosing was stopped on Day 17 and replaced with Compound 1 dosing (100 ⁇ g/kg/day) for the remainder of the study. This experiment is described in more detail in Example 15.
- FIG. 41 is a graph comparing the effect of Compound 1, dexamethasone, and the combination of Compound 1 and dexamethasone on RPMI-8226 multiple myeloma tumor volume in mice as described in Example 22.
- Dexamethasone was administered at a dose of 5 mg/kg intravenously (IV) every week (QW) and Compound 1 was administered at a dose of 10 ⁇ g/kg or 100 ⁇ g/kg orally every day.
- Compound 1 at 10 ⁇ g/kg was dosed in combination with Dexamethasone at each agent’s respective dose levels and schedules.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- FIG. 42 is a graph comparing the effect of Compound 1, dexamethasone, and the combination of Compound 1 and dexamethasone on RPMI-8226 multiple myeloma tumor volume in mice as described in Example 22.
- Dexamethasone was administered at a dose of 5 mg/kg intravenously (IV) every week (QW) and Compound 1 was administered at a dose of 10 ⁇ g/kg orally every day.
- Compound 1 was dosed in combination with dexamethasone at each agent’s respective dose levels and schedules. Once a tumor volume reached 1000 mm 3 the animal was removed from the study and recorded as a death.
- the y-axis is the probability of an animal’s survival on a particular treatment and the x-axis is the numbers of days an animal has survived.
- FIG. 43 is a graph of IKZF1, IKZF3 and IRF-4, tumor protein expression in mice injected with RECI MCL tumors and administered Compound 1 as described in Example 35.
- the x-axis is labeled with the time post dose that the animal was sacrificed, and the y-axis is the percent of protein compared to the vehicle control normalized to GAPDH.
- FIG. 44 is a graph of E2F1 and Cyclin DI, protein expression in mice injected with RECI MCL tumors and administered Compound 1 as described in Example 35.
- the x-axis is labeled with the time post dose that the animal was sacrificed, and the y-axis is the percent of protein compared to the vehicle control normalized to GAPDH.
- FIG. 45A, FIG. 45B, and FIG. 45C are dot bar graphs describing the effect of Compound 1 on growth of NHL cell lines compared to pomalidomide as described in Example 37.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM that inhibited cellular growth at 96 hr by 50% (IC 50 ) and the y-axis is the cell line tested. Open symbols indicate that growth was not inhibited by more than 50% at the highest tested concentration (100 nM or 10 ⁇ M for Compound 1, 10 ⁇ M for pomalidomide, and 10 ⁇ M for CC-92480) and therefore IC50 was not determined.
- FIG. 46 is a western blot taken from mice bearing established KLJK xenografts that were administered a single dose of Compound 1 (100 ⁇ g/kg) or daily for 5 days. Tumors were collected at 4 and 24 hours post single dose and 24 hours post 5 daily doses. Tumors were analyzed by western blot for IKZF1 and IRF-4 levels. The experimental procedure is described in Example 38.
- FIG. 47 is a line graph showing the change in tumor volume in mice bearing Mino xenograft tumors that were treated with Compound 1 (100 ⁇ g/kg) once a day orally, rituximab once a week IV (10 mg/kg), or the combination of the two at their respective doses. Data are expressed as mean tumor volumes ⁇ SEM values. The experimental procedure is described in Example 39.
- FIG. 48 is a line graph showing change in concentration over time after treating mice bearing established NCI-H929 xenograft tumors were treated with a single dose of Compound 1 (100 ⁇ g/kg) or CC-92480 (1000 ⁇ g/kg). Plasma and tumor samples were collected at 1, 4, 24, and 48 hours post single dose and analyzed by LC-MS/MS. Data are expressed total compound concentration ⁇ SEM values. The experimental procedure is provided in Example 40.
- FIG. 49 is a line graph showing change in concentration over time after treating mice bearing established NCI-H929 xenograft tumors were treated with a single dose of Compound 1 (100 ⁇ g/kg), CC-92480 (1000 ⁇ g/kg), or pomalidomide (3000 ⁇ g/kg). Tumor samples were collected at 1, 4, 24, and 48 hours post single dose and analyzed by western blot for IKZF3 levels. Data are expressed as percent of IKZF3 remaining in comparison to the vehicle control and normalized to GAPDH ⁇ SEM values. The experimental procedure is provided in Example 40.
- FIG. 50 is a line graph showing change in tumor volume over time after treating mice bearing established NCI-H929 xenograft tumors were treated with Compound 1 (100 ⁇ g/kg), CC- 92480 (1000 ⁇ g/kg), or pomalidomide (3000 ⁇ g/kg) orally daily for 18 days. Tumor volume and body weights were measured twice a week. Data are expressed as mean tumor volumes ⁇ SEM values. The experimental procedure is provided in Example 40.
- FIG. 51 is a dose-response curve describing the effect of Compound 1 on Caspase 3/7 activity in TMD8 cell line compared to pomalidomide after 48 hr treatment as described in Example 41.
- the x-axis is the concentration of Compound 1 or pomalidomide in nM and the y- axis is the luminescence signal (RLU) relative to DMSO-treated controls measured following addition of caspase 3/7 substrate reagents.
- FIG. 52 is a dose-response curve describing the effect of Compound 1 on TMD8 cell viability compared to pomalidomide after 96-hour treatment as described in Example 42.
- the x- axis is the concentration of Compound 1 or pomalidomide in nM and the y-axis is the % cellular viability relative to DMSO-treated controls measured following addition of CellTiter Gio reagents.
- FIG. 53 is a line graph demonstrating the effect of Compound 1, ibrutinib, and the combination of Compound 1 and ibrutinib on Mino mantle cell lymphoma xenograft tumors.
- Mice were administered Compound 1 at a dose of 30 ⁇ g/kg/day, ibrutinib at a dose of 25 mg/kg, the combination of ibrutinib and Compound 1 at their respective dose levels, or the vehicle control orally daily for 34 days.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- Statistics were done using a paired t test in GraphPad Prism software. The experimental procedure is provided in Example 44.
- Example 54 is a line graph demonstrating the effect of Compound 1, CC-92480, pomalidomide, or the vehicle control on RPMI-8226 multiple myeloma xenograft tumors.
- Mice were administered Compound 1 at a dose of 100 ⁇ g/kg/day, CC-92480 at 1000 ⁇ g/kg/day, or pomalidomide at 3000 ⁇ g/kg/day orally daily for 19 days.
- the x-axis is the time measured in days and the y-axis is the tumor volume measured in mm 3 .
- Statistics were done using a paired t test in GraphPad Prism software. The experimental procedure is provided in Example 45.
- FIG. 55 is a line graph demonstrating the effect of Compound 1, CC-92480, pomalidomide, or the vehicle control on IKZF3 levels in RPMI-8226 multiple myeloma xenograft tumors.
- Mice were administered Compound 1 at a dose of 100 ⁇ g/kg/day, CC-92480 at 1000 ⁇ g/kg/day, or pomalidomide at 3000 ⁇ g/kg/day orally daily for 7 days. Tumors were sampled at 4 and 24 hours post single dose, and 24 hours post 3, 5, and 7 daily doses. Data is represented as percent of target present in the vehicle control and normalized for total protein. Error bars represent ⁇ SEM values. The experimental procedure is provided in Example 45.
- FIG. 56 is a line graph demonstrating the effect of Compound 1, bortezomib, and the combination of Compound 1 and bortezomib in NCI-H929 xenografts.
- Mice bearing established NCI-H929 xenografts were administered doses of Compound 1 (10 ⁇ g/kg), bortezomib (0.5 mg/kg), the combination of Compound 1 and bortezomib, or the vehicle control for 14 days.
- Compound 1 was dosed orally daily while bortezomib was dosed on a every other week schedule intravenously.
- Statistical analysis was done on day 14, the last day all animals were on study, by two-way ANOVA using GraphPad Prism software. Data are expressed as mean tumor volumes ⁇ SEM.
- FIG. 57 is a line graph demonstrating the effect of Compound 1, bortezomib, and the combination of Compound 1 and bortezomib in NCI-H929 xenografts.
- Mice bearing established NCI-H929 xenografts were administered doses of Compound 1 (10 ⁇ g/kg), bortezomib (0.25 mg/kg), the combination of Compound 1 and bortezomib, or the vehicle control for 14 days.
- Compound 1 was dosed orally daily while bortezomib was dosed twice a week intravenously.
- Statistical analysis was done on day 14, the last day all animals were on study, by two-way ANOVA using GraphPad Prism software. Data are expressed as mean tumor volumes ⁇ SEM.
- FIG. 58 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IL2 secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 59 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IFNg secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 60 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IL21 secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 61 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IL9 secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 62 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IL4 secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 63 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of TNF-alpha secreted from anti-CD3 stimulated T-cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- FIG. 64 is a line graph containing the effect of Compound 1, Compound 2, Compound 15, CC-92480, or Pomalidomide on the concentration of IL17A secreted from anti-CD3 stimulated T- cells after a six-day incubation.
- the x-axis is the concentration of compound in nM and the y-axis is the fold-change relative to DMSO treated control wells.
- the experimental procedure is provided in Example 46.
- the new treatments, for example low dosage regimens, described herein are based on the discovery that the described compounds are unusually highly active Ikaros and Aiolos degraders. It is thought that Compound 1 is the most potent IKZF1/3 degrader publicly disclosed to date. Data described herein and otherwise obtained establishes markedly improved antitumor effect of the combination of Compound 1 and dexamethasone.
- the Compounds described herein, and notably Compound 1 are significantly more efficacious than pomalidomide across NHL models, including PTCL and MCL, both in vitro and in vivo.
- these compounds can be used in preference over thalidomide, lenalidomide, and pomalidomide, in NHL subtypes where classical IMiDs have demonstrated clinical activity but have not been widely adopted as standard of care (MCL, DLBCL, PTCL, etc ).
- the compounds described herein can be administered to treat disorders mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) in a low dosage regimen once or twice a day, optionally with a drug holiday, in highly effective treatment modalities.
- treatment can be effective for a patient using one of the compounds described herein with a dosage of not more than about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125 or even 100, 75, 50 or 25 micrograms ( ⁇ g) once a day (QD) or twice a day (BID).
- the patient is an adult (typically a human of at least 100 pounds or more, and sometimes even 125 or 150 pounds (e.g., 70 kg or more and at least typically 18 years old or more). In an alternative embodiment, the patient is pediatric (and may be less than 100, 125 or 150 pounds and typically less than 18 years old).
- the dosage includes a drug holiday.
- a drug holiday is a time period during which the patient is not administered the active compound.
- Treatment cycles, for the purposes of this disclosure are usually based on a 28 day cycle.
- the patient may be administered the active compound or its pharmaceutically acceptable salt for 21 continuous days and not administered the chemotherapeutic for 7 days during the 28 day cycle, and then optionally the regimen is repeated once or several or more times.
- one of the compounds described herein may be administered once or twice a day for at least 13, 14 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 continuous days, and then a holiday taken until the next 28 day cycle.
- the compound is administered once or twice a day for at least 20, 21, 22, 23 or 24 continuous days followed by a drug holiday until the end of the 28 day cycle.
- the drug is administered every day without a holiday to achieve continuous dosing during the dosing regimen period, which may be 1, 2, 3, or 4 weeks, or even 1, 2, 3, 4, 5 or 6 or more continual or periodic months.
- the use of a compound described herein eliminates the need for an off-cycle period, drug holiday, or reduction in co-administered anti -neoplastic compound concentration during treatment.
- the cycle period is greater than 28 days, such as greater than 30 or 35 days, and an appropriate on-cycle and off-cycle regimen determined by the patient’s healthcare specialist.
- the Ikaros (IKZF1) and/or Aiolos (IKZF3) degrader is administered in combination with one or more additional therapeutic agents.
- additional therapeutic agents include:
- a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531 , DTRMWXHS-12, JN J-64264681 , branebrutinib, ibrutinib, and fenebrutinib.
- a CD38 antibody selected from felzartamab, daratumumab, GBR 1342, TAK-573, CID- 103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.
- An IMiD selected from pomalidomide, lenalidomide, thalidomide, iberdomide CC-92480, CC-90009, and CC-99282.
- An HD AC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay 10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, 1-Alaninechlamy docin, depudecin, and CUDC-101. 6.
- the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, A-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
- the present invention includes compounds described herein with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
- Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. If isotopic substitutions are used, the common replacement is at least one deuterium for hydrogen.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 17 0, 18 O, and 18 F, respectively.
- isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- metabolic studies with, for example 14 C
- reaction kinetic studies with, for example 2 H or 3 H
- detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed
- any hydrogen atom present in the compound of the invention may be substituted with an 18 F atom, a substitution that may be particularly desirable for PET or SPECT studies.
- Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
- isotopes of carbon e.g., 13 C and 14 C, may be used.
- Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
- the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
- the substitution of a hydrogen atom for a deuterium atom can be provided in any compound described herein.
- the alkyl residue may be deuterated (in non-limiting embodiments, CDEE, CD2H, CD 3 , CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, etc ).
- the compounds of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compounds described herein.
- the term "solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
- Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
- hydrate refers to a molecular complex comprising a compound of the invention and water.
- Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, deacetone, de-DMSO.
- a solvate can be in a liquid or solid form.
- a “dosage form” means a unit of administration of an active agent.
- dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
- a “dosage form” can also include an implant, for example an optical implant.
- endogenous refers to any material from or produced inside an organism, cell, tissue or system.
- exogenous refers to any material introduced from or produced outside an organism, cell, tissue or system.
- moduleating mediating a detectable increase or decrease in the level of a response in a patient compared with the level of a response in the patient in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated patient.
- the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a patient, preferably, a human.
- Parenteral administration of a compound includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
- compositions is a composition comprising at least one active agent such as a selected active compound described herein, and at least one other substance, such as a carrier.
- “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
- a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, acid or base addition salts thereof with a biologically acceptable lack of toxicity. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
- salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
- a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
- Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
- non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable.
- Salts of the present compounds further include solvates of the compounds and of the compound salts.
- Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
- Lists of additional suitable salts may be found, e.g.,
- carrier means a diluent, excipient, or vehicle that an active agent is used or delivered in.
- a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In certain embodiments, an excipient is used that is acceptable for veterinary use.
- a “patient” or “host” is a human or non-human animal in need of treatment, of any of the disorders as specifically described herein. Typically, the host is a human.
- a “host” may alternatively refer to for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird and the like.
- a “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the compound used in the present invention is or a pharmaceutically acceptable salt thereof.
- the invention provides a treatment of an Ikaros or Aiolos mediated disorder comprising administering a low dose treatment regimen in a host in need thereof comprising administering a dose of not more than about 500, 450, 400, 350, 300, 250 200, 150 or even 100 micrograms ( ⁇ g) once a day (QD) or twice a day (BID) of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 or a pharmaceutically acceptable salt thereof.
- QD a day
- BID twice a day
- Ikaros or Aiolos mediated disorder is a cutaneous T-cell lymphoma.
- Ikaros or Aiolos mediated disorder is mantle cell lymphoma.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers, for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇ , is determined, wherein if the patient has a statistically lower concentration including but not limited to up to about 5, 10, 15 or 20% lower, of the biomarker than a healthy person then Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein is administered to the patient.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers, for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC is determined, wherein if the patient has a statistically higher concentration including but not limited to up to about 5, 10, 15 or 20% higher of biomarker than a healthy person then Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein is administered to the patient. 4.
- biomarkers for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein the patient is administered Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein and then a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers, for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇ , is determined, wherein if the concentration of the biomarker is not significantly increased, for example by at least about 1.25, 1.5, 1.75, or 2-fold, then the dose of the compound is increased.
- biomarkers for example IRF-1, caspase-3, IL-2, and/or IFN- ⁇
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein the patient is administered Compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein and then a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers, for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC is determined, wherein if the concentration of the biomarker is not significantly decreased, for example by at least about 1.25, 1.5, 1.75, or 2-fold, then the dose of the compound is increased.
- biomarkers for example cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and/or MYC
- a treatment of an Ikaros or Aiolos mediated disorder comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the Ikaros or Aiolos mediated disorder is an activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, is used in combination with a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.
- a BTK inhibitor selected from acalabrutin
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, is used in combination with a CD38 antibody selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, is used in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP- 18770, NEOSH101, TQB3602, and KZR-616.
- a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP- 18770, NEOSH101, TQB3602, and KZR-616.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, is used in combination with an IMiD selected from CC-92480, CC-90009, and CC-99282.
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, is used in combination with a HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, 1-Alaninechlamy docin, depudecin, and
- a treatment of a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, is used in combination with a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.
- any one of embodiments 1-36 wherein the compound is or a pharmaceutically acceptable salt thereof.
- the treatment of any one of embodiments 1-36, wherein the compound is or a pharmaceutically acceptable salt thereof.
- the treatment of any one of embodiments 1-36, wherein the compound is or a pharmaceutically acceptable salt thereof.
- the treatment of embodiment 50, wherein the Bruton tyrosine kinase inhibitor is ibrutinib.
- the treatment of embodiment 52, wherein the corticosteroid is dexamethasone.
- the treatment of any one of embodiments 1-49, wherein the compound is administered in conjunction with CAR T-cell therapy.
- the treatment of any one of embodiments 1-49, wherein the compound is administered in conjunction with an antibody-drug conjugate.
- the treatment of any one of embodiments 1-49, wherein the compound is administered in conjunction with BiTE therapy.
- any one of embodiments 1-49 wherein the compound is administered in conjunction with a monoclonal antibody.
- a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ- 64264681, branebrutinib, ibrutinib, and fenebrutinib.
- a CD38 antibody selected from felzartamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- any one of embodiments 1-49 wherein the compound is administered in conjunction with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG- 262, CEP-18770, NEOSH101 , TQB3602, and KZR-616.
- a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG- 262, CEP-18770, NEOSH101 , TQB3602, and KZR-616.
- an IMiD selected from pomalidomide, lenalidomide, thalidomide, iberdomide CC
- an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzam
- a treatment is provided as described above wherein the dose of Compound 1 is less than or equal to about 5 ⁇ g.
- a treatment is provided as described above wherein the dose of Compound 1 is less than or equal to about 10 ⁇ g.
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering a dose of no more than about 500 micrograms ( ⁇ g) once a day (QD) or twice a day (BID) of a compound selected from
- a method of treating a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a blood or tissue sample is taken from a patient and the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN- y, is determined, wherein if the patient has a statistically lower concentration of the biomarker(s) than a healthy person then a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof is administered to the patient, is provided.
- IKZF1 Ikaros
- IKZF3 Aiolos
- a method of treating a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a blood or tissue sample is taken from a patient and the concentration of one or more biomarkers selected from cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and MYC is determined, wherein if the patient has a statistically higher concentration of the biomarker(s) than a healthy person then a compound selected Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof is administered to the patient.
- the statistically higher concentration of the biomarker(s) is 5% higher than an average healthy patient.
- a method of treating a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a patient is administered a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, and then a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN- ⁇ , is determined, wherein if the concentration of the biomarker(s) is not significantly increased, then the dose of the compound is increased, is provided.
- IKZF1 Ikaros
- IKZF3 Aiolos
- a method of treating a disorder mediated by Ikaros (IKZF1) and/or Aiolos (IKZF3) wherein a patient is administered a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, and then a blood or tissue sample is taken from the patient and the concentration of one or more biomarkers selected from cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, and MYC is determined, wherein if the concentration of the biomarker(s) is not significantly decreased, then the dose of the compound is increased, is provided.
- IKZF1 and/or Aiolos IKZF3
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the Ikaros or Aiolos mediated disorder is an activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma, is provided.
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, wherein the patient also receives a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531 , DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib, is provided.
- a BTK inhibitor selected from acalabru
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, wherein the patient also receives a CD38 antibody selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab, is provided.
- a CD38 antibody selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, wherein the patient also receives a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP-18770, NEOSHI 01 , TQB3602, and KZR-616, is provided.
- a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP-18770, NEOSHI 01 , TQB3602, and KZR-616
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient also receives an IMiD selected from CC-92480, CC-90009, and CC-99282, is provided.
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient also receives a HD AC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, 1-Alaninechlamy doc
- a method of treating a disorder mediated by Ikaros and/or Aiolos comprising administering an effective amount of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13 or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient also receives a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab, is provided. 51.
- a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ -64264681, branebrutinib, ibrutinib, and fenebrutinib is also administered to the patient.
- a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC00
- CD38 antibody selected from felzartamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient.
- a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616 is also administered to the patient.
- the treatment includes the administration of a low dosage form once or twice a day, optionally with a drug holiday, that are highly effective treatment modalities.
- a drug holiday that are highly effective treatment modalities.
- treatment can be effective for a patient using one of the compounds described herein with a dosage of not more than about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125 or even 100, 75, 50 or 25 micrograms ( ⁇ g) once a day (QD) or twice a day (BID) optionally with a treatment holiday.
- the patient is an adult (typically a human of at least 100 pounds or more, and typically 18 years old or more).
- the patient is pediatric (and may be less than 100 pounds and typically less than 18 years old).
- the selected compound for example Compound 1 may be administered as monotherapy or may be combined with a standard of care therapy for the target tumor or cancer, including but not limited to any of those described in the Background of the Invention, or such as a proteasome inhibitor and/or an anti-CD38 monoclonal antibody (mAbs).
- MCL the selected compound can be used, for example, in combination with a Bruton tyrosine kinase (BTK) inhibitor, or an anti- CD20 monoclonal antibody.
- BTK Bruton tyrosine kinase
- PTCL in particular ALCL
- the selected compound may be administered, for example, in combination with anti-CD30 or anti-CD38 monoclonal antibody.
- Compound 1 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 2 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 3 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 4 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 5 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 6 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 7 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 8 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 9 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 10 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 11 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 12 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- Compound 13 is used to treat a disorder mediated by Ikaros or Aiolos according to a treatment regimen described herein.
- a compound described herein, for example Compound 1 is used to treat a cancer that has metastasized.
- a compound described herein, for example Compound 1 is used to treat a cancer that has metastasized to the brain.
- the dosage includes a drug holiday.
- a drug holiday is a time period during which the patient is not administered the active compound.
- the patient may be administered the active compound or its pharmaceutically acceptable salt for 21 continuous days and not administered the chemotherapeutic for 7 days during a 28 day cycle, and then optionally the regimen is repeated once, several or mor times.
- one of the compounds described herein may be administered once or twice a day for at least 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 continuous days, and then a holiday taken until the next 28 day cycle.
- the compound is administered once or twice a day for at least 20, 21, 22, 23 or 24 continuous days followed by a drug holiday until the end of the 28 day cycle.
- the drug is administered every day without a holiday to achieve continuous dosing during the dosing regimen period, which may be 2, 3, or 4 weeks, or even 1, 2, 3, 4, 5 or 6 or more continual months.
- the use of a compound described herein eliminates the need for an off-cycle period, drug holiday, or reduction in co-administered anti -neoplastic compound concentration during treatment.
- the cycle period is greater than 28 days, such as greater than 30 or 35 days.
- the compound of the present invention is administered for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered for 14 consecutive days followed by a 14-day dosage holiday. In certain embodiments, the compound of the present invention is administered for 21 consecutive days followed by a 7-day dosage holiday.
- the compound of the present invention is administered once a day for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered daily for 14 consecutive days followed by a 14-day dosage holiday. In certain embodiments, the compound of the present invention is administered daily for 21 consecutive days followed by a 7- day dosage holiday. In certain embodiments, the compound of the present invention is administered twice a day for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered twice a day for 14 consecutive days followed by a 14-day dosage holiday. In certain embodiments, the compound of the present invention is administered twice a day for 21 consecutive days followed by a 7-day dosage holiday.
- Compound 1 is administered orally daily for 21 days followed by a 7-day holiday within each 28-day treatment cycle.
- the compound of the present invention is administered at a dose of about 800 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 600 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 400 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 300 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 200 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 100 ⁇ g.
- the compound of the present invention is administered at a dose of less than about 50 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of less than about 25 ⁇ g.
- the compound of the present invention is administered at a dose of about 50 ⁇ g.
- the compound of the present invention is administered at a dose of about 45 ⁇ g.
- the compound of the present invention is administered at a dose of about 40 ⁇ g.
- the compound of the present invention is administered at a dose of about 35 ⁇ g. In certain embodiments, the compound of the present invention is administered at a dose of about 30 ⁇ g.
- the compound of the present invention is administered at a dose of about 25 ⁇ g.
- the compound of the present invention is administered at a dose of about 20 ⁇ g.
- the compound of the present invention is administered at a dose of about 15 ⁇ g.
- the compound of the present invention is administered at a dose of about 10 ⁇ g.
- the compound of the present invention is administered at a dose of about 5 ⁇ g.
- the compound of the present invention is administered at a dose of about 1 ⁇ g.
- Compound 1 is given at a dose of less than about 800 ⁇ g. In certain embodiments, Compound 1 is given at a dose of less than about 600 ⁇ g. In certain embodiments, Compound 1 is given at a dose of less than about 400 ⁇ g. In certain embodiments, Compound 1 is given at a dose of less than about 300 ⁇ g. In certain embodiments, Compound 1 is given at a dose of less than about 200 ⁇ g. In certain embodiments, Compound 1 is given at a dose of less than about 100 ⁇ g.
- Compound 1 is given at a dose of about 800 ⁇ g. In certain embodiments, Compound 1 is given at a dose of about 600 ⁇ g. In certain embodiments, Compound 1 is given at a dose of about 400 ⁇ g. In certain embodiments, Compound 1 is given at a dose of about 300 ⁇ g. In certain embodiments, Compound 1 is given at a dose of about 200 ⁇ g. In certain embodiments, Compound 1 is given at a dose of about 100 ⁇ g.
- Compound 1 is administered at a dose of at least about or between 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 25 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 50 or 75 ⁇ g.
- Compound 1 is administered at a dose of about 100 or 150 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 175 or 200 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 225 or 250 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 275, 300, 325 or 350 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 400 or 450 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 550 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 650 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 725 ⁇ g. In certain embodiments, Compound 1 is administered at a dose of about 800 ⁇ g.
- the present invention includes at least the following low-dose features:
- a low dose treatment regimen for an Ikaros or Aiolos mediated disorder in a host comprising administering a dose of not more than 500, 450, 400, 350, 300, 250 200, 150 or even 100 micrograms ( ⁇ g) once a day (QD) or twice a day (BID) to a patient in need thereof of a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13;
- (k) the treatment of (a)-(j) wherein the disorder selected from diffuse large B-cell lymphoma, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, mantle cell lymphoma, and multiple myeloma, comprising administering an effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 to a patient in need thereof;
- (x) a method of manufacturing a medicament for the treatment according to (a)-(j) of a tumor in a host, including any of the tumors described herein, characterized in that a compound described herein is used in the manufacture;
- a compound described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, for the treatment according to (a)-(j) of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin’s lymphoma, or Non-Hodgkin’s Lymphoma;
- a compound described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof in the manufacture of a medicament for the treatment according to (a)-(j) of a hematological malignancy such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin’s lymphoma, or NonHodgkin’s Lymphoma;
- (dd) a method of manufacturing a medicament for the treatment according to (a)-(j) of a hematological malignancy in a host such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin’s lymphoma, or Non-Hodgkin’s Lymphoma, characterized in that a compound described herein is used in the manufacture;
- composition comprising an effective host-treating amount according to (a)-(j) of a compound described herein or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof with a pharmaceutically acceptable carrier or diluent;
- the compound of the present invention is given at a dose of less than about 800 mg. In certain embodiments, the compound of the present invention is given at a dose of less than about 600 mg. In certain embodiments, the compound of the present invention is given at a dose of less than about 400 mg. In certain embodiments, the compound of the present invention is given at a dose of less than about 300 mg. In certain embodiments, the compound of the present invention is given at a dose of less than about 200 mg. In certain embodiments, the compound of the present invention is given at a dose of less than about 100 mg.
- the compound of the present invention is administered at a dose of about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 mg.
- the compound of the present invention is administered at a dose of about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 ⁇ g.
- the compound of the present invention is administered at a dose of at least about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 ⁇ g.
- the compound of the present invention is administered at a dose of less than least about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 ⁇ g.
- a disorder mediated by Ikaros or Aiolos is treated by Compound 1, or a pharmaceutically acceptable salt thereof, or another compound described herein.
- the cancer is a hematopoietic cancer.
- the cancer is a lymphoma, leukemia or myeloma.
- the cancer is a Non-Hodgkin’s Lymphoma or a Hodgkin’s lymphoma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat diffuse large B-cell lymphoma.
- the diffuse large B-cell lymphoma is an activated B-cell lymphoma or a germinal center B-cell lymphoma.
- the diffuse large B-cell lymphoma is a BCL2/6 translocation bearing cancer.
- the diffuse large B-cell lymphoma is a double hit bearing cancer.
- the diffuse large B-cell lymphoma is a BCL2/6 MYC wild type cancer.
- the compound of the present invention increases the concentration of Caspase-3 and/or Caspase-7. In certain embodiments this increased concentration of Caspase-3 and/or caspase-7 drives cancer cell death, for example mediating the treatment of diffuse large B- cell lymphoma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat anaplastic large cell lymphoma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat cutaneous T-cell lymphoma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat mantle cell lymphoma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat multiple myeloma.
- the compound of the present invention is administered to a patient in need thereof in an effective amount to treat a disorder that is resistant to treatment with other cereblon ligands. In certain embodiments, the compound of the present invention is used to treat an IMiD-refractory disorder.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat diffuse large B-cell lymphoma.
- the diffuse large B-cell lymphoma is an activated B-cell lymphoma or a germinal center B-cell lymphoma.
- the diffuse large B-cell lymphoma is a BCL2/6 translocation bearing cancer.
- the diffuse large B-cell lymphoma is a double hit bearing cancer.
- the diffuse large B-cell lymphoma is a BCL2/6 MYC wild type cancer.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat anaplastic large cell lymphoma.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat cutaneous T-cell lymphoma.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat mantle cell lymphoma. In certain embodiments, Compound 1 is administered to a patient in need thereof in an effective amount to treat multiple myeloma.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat a disorder that is resistant to treatment with other cereblon ligands. In certain embodiments, Compound 1 is administered to a patient in need thereof in an effective amount to treat an IMiD-refractory disorder.
- an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof is administered to a patient to treat a CNS involved cancer, for example a lymphoma in the CNS.
- a CNS involved cancer for example a lymphoma in the CNS.
- the patient with a CNS involved cancer for example a lymphoma in the CNS, is also administered one or more additional therapeutic agents, for example ibrutinib or rituximab.
- a compound described herein is used in the treatment of a peripheral central nervous system lymphoma.
- Compound 1 is administered for the treatment of PTCL-NOS (i.e. PTCL that is not otherwise specified).
- Compound 1 is administered for the treatment of PTCL with a specified subtype for example anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-Cell lymphoma (AITL), enteropathy-type T-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma.
- ACL anaplastic large cell lymphoma
- AITL angioimmunoblastic T-Cell lymphoma
- enteropathy-type T-cell lymphoma for example anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-Cell lymphoma (AITL), enteropathy-type T-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma.
- NK
- the disorder treated by a compound of the present invention is an immunomodulatory disorder. In certain embodiments, the disorder treated by a compound of the present invention is mediated by angiogenesis. In certain embodiments, the disorder treated by a compound of the present invention is related to the lymphatic system.
- a compound of the present invention or pharmaceutical salt thereof, optionally in a pharmaceutical composition as described herein is administered to a patient in need thereof in an effective amount to degrade Ikaros or Aiolos, which is a mediator of the disorder affecting the patient, such as a human.
- the control of protein level afforded by any of the compounds of the present invention provides treatment of a disease state or condition, which is modulated through Ikaros or Aiolos by lowering the level of that protein in the cell, e.g., cell of a patient, or by lowering the level of downstream proteins in the cell.
- the treatment comprises administering an effective amount of the compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternation with another bioactive agent or combination of agents.
- a pharmaceutically acceptable excipient i.e., a pharmaceutically acceptable composition
- adjuvant i.e., a pharmaceutically acceptable composition
- a compound of the present invention is administered to a patient in need thereof in an effective amount to treat a disorder including, but not limited to, benign growth, neoplasm, tumor, cancer, abnormal cellular proliferation, immune disorder, inflammatory disorder, graft- versus-host rejection, viral infection, bacterial infection, an amyloid-based proteinopathy, a proteinopathy, or a fibrotic disorder.
- a disorder including, but not limited to, benign growth, neoplasm, tumor, cancer, abnormal cellular proliferation, immune disorder, inflammatory disorder, graft- versus-host rejection, viral infection, bacterial infection, an amyloid-based proteinopathy, a proteinopathy, or a fibrotic disorder.
- disease state or “condition” when used in connection with any of the compounds is meant to refer to any disease state or condition that is mediated by Ikaros or Aiolos, such as cellular proliferation, or by proteins that are downstream of Ikaros or Aiolos, and where degradation of such protein in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof.
- the disease state or condition may be cured.
- a compound or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality.
- a compound as described herein can be administered to a host suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma.
- the host can be suffering from a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK- Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma (DSCCL); Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma; Non-Hodgkin lymphoma NOS, Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal
- a compound or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a Hodgkin lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.
- CHL Nodular Sclerosis Classical Hodgkin’s Lymphoma
- Mixed Cellularity CHL Lymphocyte-depletion CHL
- Lymphocyte-rich CHL Lymphocyte Predominant Hodgkin Lymphoma
- Lymphocyte Predominant Hodgkin Lymphoma or Nodular Lymphocyte Predominant HL.
- a compound or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with an immunomodulatory condition.
- immunomodulatory conditions include: arthritis, lupus, celiac disease, Sjogren’s syndrome, polymyalgia rheumatia, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.
- the condition treated with a compound of the present invention is a disorder related to abnormal cellular proliferation.
- Abnormal cellular proliferation notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.
- Abnormal proliferation of B-cells, T-cells, and/or NK cells can result in a wide range of diseases such as cancer, proliferative disorders and inflammatory/immune diseases.
- a host for example a human, afflicted with any of these disorders can be treated with an effective amount of a compound as described herein to achieve a decrease in symptoms (palliative agent) or a decrease in the underlying disease (a disease modifying agent).
- a compound or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclass
- a compound or its corresponding pharmaceutically salt, isotopic derivative, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a T-cell or NK-cell lymphoma such as, but not limited to: anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T- cell lymphoma, for example mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epiderm otropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid papulosis;
- ALK
- a compound or its corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug as described herein can be administered to treat a host, for example a human, with leukemia.
- the host may be suffering from an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia.
- ALL Acute lymphoblastic leukemia
- AML Acute myelogenous leukemia
- CLL Chronic lymphocytic leukemia
- CML Chronic myelogenous
- the patient suffers from an acute myelogenous leukemia, for example an undifferentiated AML (M0); myeloblastic leukemia (Ml; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 orM4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).
- M0 undifferentiated AML
- Ml myeloblastic leukemia
- M2 myeloblastic leukemia
- M3V promyelocytic leukemia
- M4 orM4 variant with eosinophilia [M4E] myelomonocytic leukemia
- M5 monocytic leukemia
- M6
- Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis.
- Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
- hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
- Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
- Fibrotic disorders are often due to the abnormal formation of an extracellular matrix.
- fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders.
- Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
- Hepatic cirrhosis can cause diseases such as cirrhosis of the liver.
- An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
- Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
- Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
- Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE.
- Bechet CAD
- ARDS acute respiratory distress syndrome
- ischemic heart disease CAD
- postdialysis syndrome CAD
- leukemia CAD
- acquired immune deficiency syndrome CAD
- vasculitis lipid histiocytosis
- septic shock inflammation in general.
- a compound or its pharmaceutically acceptable salt, isotopic analog, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a proliferative condition such as myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), system mast cell disease (SMCD), and the like.
- MPD myeloproliferative disorder
- PV polycythemia vera
- ET essential thrombocythemia
- MMM myeloid metaplasia with myelofibrosis
- CMML chronic myelomonocytic leukemia
- HES hypereosinophilic syndrome
- SMCD system mast cell disease
- a compound provided herein is useful for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myelogenous leukemia.
- a compound or its pharmaceutically acceptable salt, isotopic analog, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a myelodysplastic syndrome (MDS) such as, but not limited to: refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts - thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD) including RCMD with multilineage dysplasia and ring sideroblasts (RCMD-RS), Refractory amenias with excess blasts I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia of childhood, and the like.
- MDS myelodysplastic syndrome
- a compound of the present invention can provide a therapeutic effect by direct degradation of Ikaros or Aiolos which may change the transcriptional regulation of a protein downstream of Ikaros or Aiolos.
- neoplasia or “cancer” is used to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
- Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
- the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
- Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's Lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendro
- Additional cancers which may be treated using compounds according to the present invention include, for example, T- lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B- cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
- T-ALL T- lineage Acute lymphoblastic Leukemia
- T-LL T-lineage lymphoblastic Lymphoma
- Peripheral T-cell lymphoma Peripheral T-cell lymphoma
- Adult T-cell Leukemia Pre-B ALL
- Pre-B Lymphomas Large B- cell Lymphoma
- Burkitts Lymphoma B-cell ALL
- Philadelphia chromosome positive ALL Philadelphia chromosome positive CML.
- Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
- a compound or its pharmaceutically acceptable salt, isotopic derivative or prodrug as described herein can be used in an effective amount to treat a host, for example a human, with an autoimmune disorder.
- a host for example a human
- an autoimmune disorder examples include, but are not limited to: Acute disseminated encephalomyelitis (ADEM); Addison's disease; Agammaglobulinemia; Alopecia areata; Amyotrophic lateral sclerosis (Also Lou Gehrig's disease; Motor Neuron Disease); Ankylosing Spondylitis; Antiphospholipid syndrome; Antisynthetase syndrome; Atopic allergy; Atopic dermatitis; Autoimmune aplastic anemia; Autoimmune arthritis; Autoimmune cardiomyopathy; Autoimmune enteropathy; Autoimmune granulocytopenia; Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune hypoparathyroidism; Autoimmune inner
- Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity.
- Others include atopic dermatitis, eczema, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
- immunologically mediated leukocyte infiltration In atopic dermatitis, and eczema in general, immunologically mediated leukocyte infiltration (particularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin importantly contributes to the pathogenesis of these diseases. Chronic eczema also is associated with significant hyperproliferation of the epidermis. Immunologically mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis sicca.
- a compound or its pharmaceutically acceptable salt, isotopic variant, or prodrug as described herein can be administered in an effective amount to treat a host, for example a human, with a skin disorder such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
- a skin disorder such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
- a skin disorder such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
- certain substances including some pharmaceuticals when topically applied can
- compounds of the present invention are used as topical agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
- Disease states of conditions which may be treated using compounds according to the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease 1 (PKD1) or 2 (PKD2) Prader- Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome.
- autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error,
- Further disease states or conditions which may be treated by compounds according to the present invention include Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.
- Alzheimer's disease Amyotrophic lateral sclerosis
- Still additional disease states or conditions which can be treated by compounds according to the present invention include aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Co/z, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1 -antitrypsin deficiency, alpha- 1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alstrbm syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson -Fabry disease, androgen insensitivity syndrome, Anemia Angio
- a treatment for treating multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition for use in a treatment of multiple myeloma, wherein the treatment comprises administering the compound to a patient.
- a treatment for managing the progression of multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition for use in a treatment for managing the progression of multiple myeloma, wherein the treatment comprises administering the compound to a patient.
- Treatments are also provided for patients who have been previously treated for multiple myeloma but are non-responsive to standard therapies in addition to those who have not been previously treated. Additional treatments are provided for patients who have undergone surgery in an attempt to treat multiple myeloma in addition to those who have not undergone surgery. Treatments are also provided for patients who have previously undergone transplant therapy in addition to those who have not.
- the disorder treated by the present invention is a wild-type cancer, wherein the term “wild-type” refers to a cancer that has not developed resistance to a previously effective treatment (i.e. a relapsed cancer) and does not have any resistance imparting mutations (i.e. a refractory cancer).
- the disorder treated by the present invention is a relapsed cancer.
- the disorder treated by the present invention is a refractory cancer.
- the disorder treated by the present invention is a relapsed and refractory cancer.
- a compound described herein for example, Compound 1 or a pharmaceutically acceptable salt thereof, can be administered in the treatment or management of multiple myeloma or NonHodgkin’s Lymphoma that is relapsed, refractory, or resistant.
- the disorder is primary, secondary, tertiary, quadruply or quintuply relapsed.
- the compounds described herein may be used to reduce, maintain, or eliminate minimal residual disease (MRD).
- multiple myeloma that may be treated with the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance (MGUS); low risk, intermediate risk, or high risk multiple myeloma; newly diagnosed multiple myeloma, including low risk, intermediate risk, or high risk newly diagnosed multiple myeloma); transplant eligible and transplant ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including low risk, intermediate risk, or high risk smoldering multiple myeloma); active multiple myeloma; solitary plasmocytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secretory myeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma.
- MGUS monoclonal gammopathy of undetermined significance
- a treatment for managing multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as induction therapy.
- a treatment for treating or managing multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as consolidation therapy.
- a method for treating or managing multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as maintenance therapy.
- the multiple myeloma is plasma cell leukemia.
- the multiple myeloma is high risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is relapsed or refractory. In certain embodiments, the high-risk multiple myeloma has relapsed within 12 months of the first treatment. In another embodiment, the high-risk multiple myeloma is characterized by genetic abnormalities, for example, one or more of del(l 7/17p) and t(14;16)(q32;q32). In some embodiments, the high risk multiple myeloma is relapsed or refractory to one, two or three previous treatments. In some embodiments, the multiple myeloma is transplant eligible newly diagnosed multiple myeloma. In other embodiments, the multiple myeloma is transplant ineligible newly diagnosed multiple myeloma.
- the multiple myeloma shows early progression (for example less than 12 months) following initial treatment. In other embodiments, the multiple myeloma shows early progression (for example less than 12 months) following autologous stem cell transplant. In another embodiment, the multiple myeloma is refractory to lenalidomide. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (for example, by molecular characterization).
- the multiple myeloma is relapsed or refractory to 3 or more treatments and was exposed to a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or double refractory to a proteasome inhibitor and an immunomodulatory compound.
- a proteasome inhibitor for example, bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib
- an immunomodulatory compound for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide
- the multiple myeloma is relapsed or refractory to 3 or more prior therapies, including for example, a CD38 monoclonal antibody (CD38 mAb, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide) or double refractory to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb.
- CD38 mAb for example, daratumumab or isatuximab
- a proteasome inhibitor for example, bortezomib, carfilzomib, ixazomib, or marizomib
- an immunomodulatory compound for example thalidomide, lenalidomide,
- the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), an immunomodulatory compound (for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), and one other active agent, as described herein.
- a proteasome inhibitor for example, bortezomib, carfilzomib, ixazomib, oprozomib or marizomib
- an immunomodulatory compound for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide
- a treatment for managing relapsed or refractory multiple myeloma in patients with impaired renal function or a symptom thereof comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a treatment for managing relapsed or refractory multiple myeloma in frail patients comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized by ineligibility for induction therapy or intolerance to dexamethasone treatment.
- the frail patient is elderly, for example, older than 65 years old.
- a treatment for managing fourth line relapsed or refractory multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a treatment for managing newly diagnosed, transplant- ineligible multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a treatment for managing newly diagnosed, transplant- ineligible multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as maintenance therapy after another therapy or transplant.
- a treatment for managing high risk multiple myeloma that is relapsed or refractory to one, two, or three previous treatments comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- the disorder treated by the present invention is a relapsed and/or refractory Non-Hodgkin’s Lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed Non-Hodgkin’s Lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory Non-Hodgkin’s Lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory Non-Hodgkin’s Lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is a relapsed multiple myeloma. In certain embodiments, the disorder treated by the present invention is a refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory multiple myeloma.
- the disorder treated by the present invention is a relapsed and/or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory peripheral T-cell lymphoma.
- Compound 1 is administered for the treatment of PTCL-NOS (i.e. PTCL that is not otherwise specified).
- Compound 1 is administered for the treatment of PTCL with a specified subtype for example anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-Cell lymphoma (AITL), enteropathy-type T-cell lymphoma, or extranodal natural killer (NK) cell/T-cell lymphoma.
- ACL anaplastic large cell lymphoma
- AITL angioimmunoblastic T-Cell lymphoma
- NK extranodal natural killer
- the disorder treated by the present invention is a relapsed and/or refractory systemic anaplastic large cell lymphoma (ALK + ). In certain embodiments, the disorder treated by the present invention is a relapsed systemic anaplastic large cell lymphoma (ALK + ). In certain embodiments, the disorder treated by the present invention is a refractory systemic anaplastic large cell lymphoma (ALK + ). In certain embodiments, the disorder treated by the present invention is a relapsed and refractory systemic anaplastic large cell lymphoma (ALK + ).
- the disorder treated by the present invention is a relapsed and/or refractory systemic anaplastic large cell lymphoma (ALK‘). In certain embodiments, the disorder treated by the present invention is a relapsed systemic anaplastic large cell lymphoma (ALK‘). In certain embodiments, the disorder treated by the present invention is a refractory systemic anaplastic large cell lymphoma (ALK‘). In certain embodiments, the disorder treated by the present invention is a relapsed and refractory systemic anaplastic large cell lymphoma (ALK‘).
- the disorder treated by the present invention is a relapsed and/or refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and/or refractory anaplastic large cell lymphoma.
- the disorder treated by the present invention is a relapsed anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory anaplastic large cell lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory mantle cell lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed follicular lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory follicular lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory follicular T-cell lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory peripheral T-cell lymphoma.
- the disorder treated by the present invention is a relapsed and/or refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is a relapsed and refractory diffuse large B-cell lymphoma.
- Compound 1 is administered to a patient in need thereof in an effective amount to treat follicular T-cell lymphoma. In certain embodiments, Compound 1 is administered to a patient in need thereof in an effective amount to treat angioimmunoblastic T-cell lymphoma. In certain embodiments, Compound 1 is administered to a patient in need thereof in an effective amount to treat systemic anaplastic large cell lymphoma (ALK‘). In certain embodiments, Compound 1 is administered to a patient in need thereof in an effective amount to treat systemic anaplastic large cell lymphoma (ALK + ).
- Non-Hodgkin’s Lymphomas that can be treated with a compound described herein include Double hit lymphoma, triple hit lymphoma, extranodal marginal zone B- cell lymphoma of MALT, extranodal NK/T-cell lymphoma, and myeloid-lineage lymphoma.
- the compound of the present invention is administered in an effective amount to treat a patient with a cereblon-mediated disorder comprising administering to the patient an effective amount of the compound and monitoring the concentration of a biomarker selected from IRF-1, caspase- 1, caspase-3, caspase-7, cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, MYC, IL-2, T-cell activation and/or proliferation, BCMA, M-protein, PARP, BIM, survivin, IKZF1, IKZF3, ZFP91, WIZ, and/or IFN- y or a combination thereof.
- a biomarker selected from IRF-1, caspase- 1, caspase-3, caspase-7, cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, MYC, IL-2, T-cell activation and/or proliferation, BCMA, M-protein, PARP, BIM, survivin, IKZF1, IK
- the concentration of IRF-1 and/or caspase 3 increases upon treating a patient with a compound described herein.
- the size of the increase can be used to determine whether or not the dose of the compound described herein should be increased, decreased, or kept the same. For example, if the concentration of IRF-1 and/or caspase 3 increases by less than 1.25, 1.5, 1.75, or 2-fold then the physician may increase the dose of Compound 1 administered to a patient being treated for a lymphoma.
- the concentration of cyclin D and/or E2F1 decreases upon treating a patient with a compound described herein.
- the size of the decrease can be used to determine whether or not the dose of the compound described herein should be increased, decreased, or kept the same. For example, if the concentration of cyclin D and E2F1 decreases by less than 1.25, 1.5, 1.75, or 2-fold then the physician may increase the dose of Compound 1 administered to a patient being treated for a lymphoma.
- the concentration of cyclin D, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and/or MYC decreases upon treating a patient with a compound described herein.
- the patient has a lymphoma. The size of the decrease can be used to determine whether or not the dose of the compound described herein should be increased, decreased, or kept the same.
- the concentration of IL-2 and/or IFN- y increases upon treating a patient with a compound described herein.
- the patient has a myeloma. The size of the increase can be used to determine whether or not the dose of the compound described herein should be increased, decreased, or kept the same.
- the concentration of the biomarker increases by about 3, 4, 5, 6, 7, or 8 fold upon delivery of an effective dose of a compound described herein, for example Compound 1.
- a compound described herein for example Compound 1.
- the activity level of caspase-3 and caspase-7 is increased by more than 800% upon treatment of Compound 1.
- the level of caspase 3/7 activity is assayed and if less than about 2, 3, 4, 5, 6, 7, or 8-fold then the dose of Compound 1 is increased.
- biomarker is STAT3.
- the biomarker is Ki67.
- the concentration of the biomarker decreases by about 3, 4, 5, 6, 7, or 8-fold upon delivery of an effective dose of a compound described herein, for example Compound 1.
- the patient treated with a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, is selected based on the concentration of a biomarker.
- the patient treated with Compound 1 may be selected based on the concentration of a biomarker.
- the biomarker is selected from IKZF1, IKZF3, MYC, il2, INFy, TNFa, sFLC, and sBCMA.
- the biomarker is selected from IRF-1, caspase-3, cyclin DI, E2F1, ZFP91, SALL4, IRF-4, BLIMP 1, MYC, IL-2, and/or IFN- y.
- the biomarker is a tumor immunity marker (e.g., a cytokine, tumor infiltrating lymphocyte, T-cell activation and/or proliferation, and B-cell markers such as BCMA or M-protein, or a combination thereof).
- the biomarker is an apoptotic marker (e.g., total and/or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM, or survivin, or a combination thereof).
- an apoptotic marker e.g., total and/or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM, or survivin, or a combination thereof.
- the biomarker is a zinc finger protein (e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof).
- a zinc finger protein e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof.
- a treatment described herein has one or more advantages over presently approved treatments of cancer, for example treatments of multiple myeloma or Non-Hodgkin’s Lymphoma.
- Compound 1 or a pharmaceutically acceptable salt thereof as administered using the treatments described herein has a better outcome in one or more of the measures described below than currently approved treatments, for example thalidomide, pomalidomide or lenalidomide (see Examples 9 12 13 15-19, 26-31, and 35 demonstrating the superior efficacy of Compound 1 in multiple myeloma and Non-Hodgkin’s Lymphoma models).
- the advantage provided by Compound 1 over currently known treatments is a decreased propensity to develop resistance.
- mice that had developed resistance to treatment with pomalidomide still responded rapidly to treatment with Compound 1 (see Figure 40). Additionally, when treatment was withdrawn from mice for a long enough period for their tumors to regrow and rechallenged with Compound 1 the tumors still rapidly decreased in size (see Figure 33).
- the advantage over currently approved therapies is the ability to treat refractory tumors.
- mice doses of Compound 1 as low as 30 ⁇ g/kg were effective in the treatment of NCLH929 tumors that were nonresponsive to 3,000 ⁇ g/kg dosing (see Figure 33).
- Compound 1 was consistently 2-3 magnitudes more potent than pomalidomide and even demonstrated efficacy against cells that were refractory to pomalidomide (see Figure 32). This effect is also demonstrated by tracking biomarkers concentration such as caspase 3 (see Figure 31).
- the advantage over currently approved therapies is a more rapid degradation of IKZF1 and IKZF3 and thus a more rapid treatment of cancer.
- Compound 1 degrades more IKZF1 in one hour than pomalidomide degrades in two hours when dosed at the same concentration (see Figure 29).
- a treatment for inducing a therapeutic response as assessed by the International Uniform Response Criteria (IURC) for Multiple Myeloma (described in Durie B. G. M; et al. “International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10): 1-7) in a patient having multiple myeloma comprising administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- IURC International Uniform Response Criteria
- a treatment is provided to achieve a stringent complete response, complete response, or very good partial response, as assessed by the IURC for Multiple Myeloma in a patient having multiple myeloma comprising administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
- a treatment is provided to achieve an increase in overall survival, progression-free survival, event-free survival, time to process, or disease-free survival in a patient having multiple myeloma comprising administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition (see Examples 21 and 22 which demonstrate a dose dependent increase in overall survival in animal models).
- Compound 1 can be further enhanced by administering an additional bioactive agent in combination therapy.
- an additional bioactive agent in combination therapy.
- mouse studies when Compound 1 was administered in a treatment regimen that included weekly dexamethasone it was far more efficacious than the same dose of Compound 1 or dexamethasone alone (see Figure 41).
- a compound described herein is administered in an effective amount to treat a cancer that is mediated by a protein with one or more mutations, for example a multiple myeloma mediated by a protein with one or more mutations.
- the compounds described herein may be administered in an effective amount in the treatment or management of multiple myeloma characterized by a genetic abnormality, for example but not limited to: Cyclin D translocations (for example, t(l I;14)(ql3;q32); t(6; 14)(p21;32); t(12; 14)(pl3;q32); or t(6;20);); MMSET translocations (for example t(4;14)(pl6;q32); MAF translocations (for example t(14;16)(q32;a32); t(20;22); t(16;22)(ql l;ql3); or t(14;20)(q32;ql 1
- the multiple myeloma has a p53 mutation.
- the p53 mutation is a Q331 mutation. In certain embodiments, the p53 mutation is a R273H mutation. In certain embodiments, the p53 mutation is a K132 mutation. In certain embodiments, the p53 mutation is a K132N mutation. In certain embodiments, the p53 mutation is a R337 mutation. In certain embodiments, the p53 mutation is a R337L mutation. In certain embodiments, the p53 mutation is a W146 mutation. In certain embodiments, the p53 mutation is a S261 mutation. In certain embodiments, the p53 mutation is a S261T mutation.
- the p53 mutation is a E286 mutation. In certain embodiments, the p53 mutation is a E286K mutation. In certain embodiments, the p53 mutation is a R175 mutation. In certain embodiments, the p53 mutation is a R175H mutation. In certain embodiments, the p53 mutation is a E258 mutation. In certain embodiments, the p53 mutation is a E258K mutation. In certain embodiments, the p53 mutation is a Al 61 mutation. In certain embodiments, the p53 mutation is a A161T mutation.
- the multiple myeloma has a homozygous deletion of p53. In certain embodiments, the multiple myeloma has a homozygous deletion of wild-type p53. In certain embodiments, the multiple myeloma has wild-type p53.
- the multiple myeloma shows activation of one or more oncogenic drivers.
- the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, Cyclin DI, and Cyclin D.
- the multiple myeloma shows activation of C-MAF.
- the multiple myeloma shows activation of MAFB.
- the multiple myeloma shows activation of FGFR3 and MMset.
- the multiple myeloma shows activation of C-MAF, FGFR3, and MMset.
- the multiple myeloma shows activation of Cyclin DI.
- the multiple myeloma shows activation of MAFB and Cyclin DI. In certain embodiments, the multiple myeloma shows activation of Cyclin D. In certain embodiments, the multiple myeloma has one or more chromosomal translocations. In certain embodiments, the chromosomal translocation is t(14;16). In certain embodiments, the chromosomal translocation is t(14;20). In certain embodiments, the chromosomal translocation is t(4; 14). In certain embodiments, the chromosomal translocations are t(4;14) and t(14;16). In certain embodiments, the chromosomal translocation is t(l l;14).
- the chromosomal translocation is t(6;20). In certain embodiments, the chromosomal translocation is t(20;22). In certain embodiments, the chromosomal translocations are t(6;20) and t(20;22). In certain embodiments, the chromosomal translocation is t(16;22). In certain embodiments, the chromosomal translocations are t(14;16) and t(16;22). In certain embodiments, the chromosomal translocations are t(14;20) and t(l 1 ; 14).
- the multiple myeloma has a Q331 p53 mutation, activation of C- MAF, and a chromosomal translocation at t(14; 16). In certain embodiments, the multiple myeloma has homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t( 14; 16). In certain embodiments, the multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20).
- the multiple myeloma has wild type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4; 14). In certain embodiments, the multiple myeloma has wild type p53, activation of C-MAF, and a chromosomal translocation at t(14; 16). In certain embodiments, the multiple myeloma has homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t(4;14) and t(14;16).
- the multiple myeloma has homozygous deletion of p53, activation of CyclinDl, and a chromosomal translocation att(l 1 ; 14). In certain embodiments, the multiple myeloma has a R337L p53 mutation, activation of Cyclin DI, and a chromosomal translocation at t(l 1; 14). In certain embodiments, the multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4; 14).
- the multiple myeloma has a S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In certain embodiments, the multiple myeloma has a E286K p53 mutation, by activation of FGFR3 and MMset, and a chromosomal translocation at t(4; 14). In certain embodiments, the multiple myeloma has a R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4; 14).
- the multiple myeloma has a E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In certain embodiments, the multiple myeloma has wild type p53, activation of MAFB and Cyclin DI, and chromosomal translocations att(14;20) and t(l 1 ; 14). In certain embodiments, the multiple myeloma has a A161T p53 mutation, activation of Cyclin D, and a chromosomal translocation at t(l 1 ; 14).
- the patient treated with a compound described herein has received a prior treatment with an IMiD, for example thalidomide, lenalidomide, or pomalidomide.
- an IMiD for example thalidomide, lenalidomide, or pomalidomide.
- the patient treated with a compound described herein has received a prior treatment with an CD20 antibody for example rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab, tositumomab, or ublituximab.
- an CD20 antibody for example rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab, tositumomab, or ublituximab.
- the patient treated with a compound described herein has received a prior treatment with an CD38 antibody for example daratumumab or isatuximab.
- an CD38 antibody for example daratumumab or isatuximab.
- the patient treated with a compound described herein has received a prior treatment with an CD30 antibody for example brentuximab.
- the patient treated with a compound described herein has received a prior treatment with a BTK inhibitor for example ibrutinib, acalabrutinib, or zanubrutinib.
- a BTK inhibitor for example ibrutinib, acalabrutinib, or zanubrutinib.
- the patient treated with a compound described herein has received a prior treatment with an alkylator for example cyclophosphomide, melphan, melphalan flufenamide, or bendamustine.
- an alkylator for example cyclophosphomide, melphan, melphalan flufenamide, or bendamustine.
- the patient treated with a compound described herein has received a prior treatment with a proteasome inhibitor for example bortezomib, carfilzomib, or ixazomib.
- a proteasome inhibitor for example bortezomib, carfilzomib, or ixazomib.
- the patient treated with a compound described herein has received a prior treatment with a glucocorticoid, for example dexamethasone, predinisone, or methylpredni sol one .
- a glucocorticoid for example dexamethasone, predinisone, or methylpredni sol one .
- the patient treated with a compound described herein has received a prior treatment with a bone-modifying agent, for example denosumab, zoledronic acid, or pamidronate.
- a bone-modifying agent for example denosumab, zoledronic acid, or pamidronate.
- the patient treated with a compound described herein has received a prior treatment with a HD AC inhibitor, for example panobinostat.
- a HD AC inhibitor for example panobinostat.
- the patient treated with a compound described herein has received a prior treatment with a nuclear export inhibitor, for example selinexor.
- the patient treated for multiple myeloma has received at least 1, 2, 3, or 4 prior anti-myeloma or lymphoma regimens, for example lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, or an anti-CD38 antibody.
- a patient that has received at least 3 prior anti-myeloma regimens including at least two consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, or an anti-CD38 antibody.
- the patient treated for multiple myeloma has a M-protein level of > about ,5g/dL by serum protein electophoresis (sPEP), >200mg/24-hour urine collection by Urine Protein Electrophoresis (uPEP), Serum Free Light Chain (FLC) levels >100 mg/L involved light chain and an abnormal kappa/lambda (K/X) ratio in subjects without measurable serum or urine M- protein, and/or a serum IgA level > 0.50g/dL.
- serum protein electophoresis sPEP
- uPEP Urine Protein Electrophoresis
- FLC Serum Free Light Chain
- K/X abnormal kappa/lambda
- the patient treated has peripheral t-cell lymphoma and has had at least one prior alkylator-based chemotherapy treatment.
- the patient treated has anaplastic large cell lymphoma (ALCL) and has had at least one prior alkylator-based chemotherapy treatment and also has received CD30 antibody therapy.
- ACL anaplastic large cell lymphoma
- the patient treated has mantle cell lymphoma and has had at least two prior lines of therapy, including a CD20 antibody and alkylator chemotherapy line, and a Bruton’s tyrosine kinase inhibitor.
- the patient treated has follicular lymphoma and has had at least two prior lines of therapy, including a CD20 antibody and alkylator chemotherapy line.
- the patient treated has diffuse large B-cell lymphoma and has had at least two prior lines of therapy, including a CD20 antibody therapy and has received a prior autologous bone marrow transplant (or is ineligible for bone marrow transplant).
- the patient treated for Non-Hodgkin’ s Lymphoma has a lesion that can be measured in at least two dimensions with PET-CT, for example a lesion with a minimum measurement of at least about 15 mm in the longest diameter.
- the patient to be treated by one of the compounds described herein has not be treated with multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated by one of the compounds described herein has been treated by multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated by one of the compounds described herein has developed drug resistant to the multiple myeloma therapy.
- the patient to be treated by one of the compounds described herein has developed resistance to one, two, or three multiple myeloma therapies, wherein the therapies are selected from a CD38 antibody (CD38 mAB, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide).
- CD38 antibody CD38 mAB
- a proteasome inhibitor for example, bortezomib, carfilzomib, ixazomib, or marizomib
- an immunomodulatory compound for example thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide.
- the compounds described herein can be administered in an effective amount to treat a patient regardless of patient’s age.
- the patient is 18 years or older. In other embodiments, the patient is more than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the patient is less than 65 years old. In other embodiments, the patient is more than 65 years old. In certain embodiments, the patient is an elderly multiple myeloma patient, such as a patient older than 65 years old. In certain embodiments, the patient is an elderly multiple myeloma patient, such as a patient older than 75 years old.
- any of the compounds described herein can be administered in an effective amount alone or in combination to treat a host such as a human with a disorder as described herein.
- a compound described herein is administered with an additional bioactive agent.
- bioactive agent is used to describe an agent, other than the compound according to the present invention, which can be administered in combination or alternation with a compound of the present invention to achieve a desired result of therapy.
- the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter.
- the compound of the present invention and the bioactive agent are administered to a host in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other.
- a compound when administered in combination with another this combination can be as one dosage form or multiple dosage forms at the same time or different times. Additionally, the compounds administered in combination can be administered with different dosing schedules.
- the combination of Compound 1 with dexamethasone includes a treatment regimen where Compound 1 is administered once a day for 21 consecutive days in a 28 day treatment cycle and dexamethasone is administered once a week during the treatment cycle.
- Compound 1 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 2 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 3 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 4 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 5 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 6 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 7 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 8 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 9 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 10 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 11 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 12 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Compound 13 is administered to a patient in need thereof in an effective amount in combination with one or more additional therapeutic agents described herein.
- Corticosteroids are compounds described herein.
- the compound of the present invention is administered in combination with a corticosteroid.
- the corticosteroid is dexamethasone.
- Compound 1 is administered with a corticosteroid.
- Compound 1 is administered with dexamethasone, for example in the dosage regimen shown below:
- Compound 1 is dosed QD on a dosing 21/7 schedule for each 28-day cycle in combination with another bioactive agent, for example once a week dosing of dexamethasone.
- the dexamethasone dose for an adult ⁇ 75 years old is 40 mg QW on days 1, 8, 15, and 22 of a 28-day cycle.
- the dexamethasone dose for an adult > 75 years old is 20 mg QW on days 1, 8, 15, and 22 of a 28- day cycle.
- a compound described herein is administered in combination with a corticosteroid.
- corticosteroids include dexamethasone, prednisone, fludrocortisone, hydrocortisone, cortisone, betamethasone, methylprednisolone.
- Compound 1 is administered in combination with a corticosteroid.
- Compound 2 is administered in combination with a corticosteroid.
- Compound 3 is administered in combination with a corticosteroid.
- Compound 4 is administered in combination with a corticosteroid.
- Compound 5 is administered in combination with a corticosteroid.
- Compound 6 is administered in combination with a corticosteroid.
- Compound 7 is administered in combination with a corticosteroid.
- Compound 8 is administered in combination with a corticosteroid.
- Compound 9 is administered in combination with a corticosteroid.
- Compound 10 is administered in combination with a corticosteroid.
- Compound 11 is administered in combination with a corticosteroid.
- Compound 12 is administered in combination with a corticosteroid.
- Compound 13 is administered in combination with a corticosteroid.
- the corticosteroid is dexamethasone.
- corticosteroids include corticosterone, aldosterone, prednisolone, triamcinolone, budesonide, deflazacort, flugestone, fluoromethoIone, medrysone, prebediolone acetate, chloroprednisone, cloprednol, difluprednate, fluocinolone, fluperolone, fluperolone acetate, fluprednisolone, loteprednol, prednicarbate, tixocortol, alclometasone, alclometasone dipropionate, beclometasone, clobetasol, clobetasone, clocortolone, desoximetasone, diflorasone, diflorasone diacetate, difluocortolone, difl uocort clone valerate, fluprednidene
- the bioactive agent is a kinase inhibitor, for example a Bruton’s tyrosine kinase (BTK) inhibitor.
- the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’ s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
- PI3K phosphoinositide 3-kinase
- BTK Bruton’ s tyrosine kinase
- Syk spleen tyrosine kinase
- the compound of the present invention is administered in combination with a BTK inhibitor.
- the BTK inhibitor is Ibrutinib.
- the embodiments the BTK inhibitor is Acalabrutinib.
- Compound 1 is administered in combination with a BTK inhibitor.
- Compound 1 is administered in combination BTK inhibitor is Zanubrutinib. In certain with Ibrutinib.
- Compound 1 is administered in combination with Zanubrutinib.
- Compound 1 is administered in combination with Acalabrutinib.
- Compound 2 is administered in combination with a BTK inhibitor.
- Compound 3 is administered in combination with a BTK inhibitor.
- Compound 4 is administered in combination with a BTK inhibitor.
- Compound 5 is administered in combination with a BTK inhibitor.
- Compound 6 is administered in combination with a BTK inhibitor.
- Compound 7 is administered in combination with a BTK inhibitor.
- Compound 8 is administered in combination with a BTK inhibitor.
- Compound 9 is administered in combination with a BTK inhibitor.
- Compound 10 is administered in combination with a BTK inhibitor.
- Compound 11 is administered in combination with a BTK inhibitor.
- Compound 12 is administered in combination with a BTK inhibitor.
- Compound 13 is administered in combination with a BTK inhibitor.
- the BTK inhibitor is selected from Ibrutinib, Zanubrutinib, and Acalabrutinib. ⁇
- BTK inhibitors examples include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(l- [(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en- 1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin- 1 -yl)-2-
- RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3- ⁇ l-methyl-5-[5-(4-methyl-piperazin-l- yl)-pyridin-2-ylamino]-6-oxo-l,6-dihydro-pyridin-3-yl ⁇ -phenyl)-2H-isoquinolin-l-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference.
- the BTK inhibitor is selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.
- Compound 1 is administered in combination with an BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO- 305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.
- an BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO- 305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011,
- PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC- 907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-Isopropyl- 5-methyl-l,2,4-triazol-3-yl)-5,6-dihydroimidazo[l,2-d][1,4]benzoxazepin-9-yl]pyrazol-l-yl]-2- methylpropanamide), MLN-1117 ((2R)-l-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl (oxo) ⁇ [(2R)-l-phenoxy-2-butanyl]oxy
- Syk inhibitors include, for example, Cerdulatinib (4-(cyclopropylamino)-2-((4-(4- (ethylsulfonyl)piperazin-l-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(lH- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[l,2-a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5- Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3- dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5
- the compound of the present invention is administered in combination with a proteasome inhibitor.
- the proteasome inhibitor is Bortezomib.
- the proteasome inhibitor is Ixazomib.
- the proteasome inhibitor is Carfilzomib.
- Compound 1 is administered in combination with a proteasome inhibitor.
- Compound 1 is administered in combination with Bortezomib.
- Compound 1 is administered in combination with Ixazomib.
- Compound 1 is administered in combination with Carfilzomib.
- Compound 1 is administered in combination with carfilzomib and daratumumab.
- Compound 2 is administered in combination with a proteasome inhibitor.
- Compound 3 is administered in combination with a proteasome inhibitor.
- Compound 4 is administered in combination with a proteasome inhibitor.
- Compound 5 is administered in combination with a proteasome inhibitor.
- Compound 6 is administered in combination with a proteasome inhibitor.
- Compound 7 is administered in combination with a proteasome inhibitor.
- Compound 8 is administered in combination with a proteasome inhibitor.
- Compound 9 is administered in combination with a proteasome inhibitor.
- Compound 10 is administered in combination with a proteasome inhibitor.
- Compound 11 is administered in combination with a proteasome inhibitor.
- Compound 12 is administered in combination with a proteasome inhibitor.
- Compound 13 is administered in combination with a proteasome inhibitor.
- the proteasome inhibitor is selected from Bortezomib, Ixazomib, VLX1570, and Carfilzomib.
- proteasome inhibitors include ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.
- Compound 1 is administered in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MGI32, MG-262, CEP-18770, NEOSH101, TQB3602, VLX1570, and KZR-616.
- the compound of the present invention is administered in combination with an HD AC inhibitor.
- the HD AC inhibitor is Vorinostat.
- the HD AC inhibitor is Romidepsin.
- the HD AC inhibitor is Panobinostat.
- the HDAC inhibitor is Belinostat.
- Compound 1 is administered in combination with an HDAC inhibitor.
- Compound 1 is administered in combination with Vorinostat.
- Compound 1 is administered in combination with Romidepsin.
- Compound 1 is administered in combination with Panobinostat.
- Compound 1 is administered in combination with Belinostat.
- Compound 2 is administered in combination with a HDAC inhibitor.
- Compound 3 is administered in combination with a HDAC inhibitor.
- Compound 4 is administered in combination with a HDAC inhibitor.
- Compound 5 is administered in combination with a HDAC inhibitor.
- Compound 6 is administered in combination with a HDAC inhibitor.
- Compound 7 is administered in combination with a HDAC inhibitor.
- Compound 8 is administered in combination with a HDAC inhibitor.
- Compound 9 is administered in combination with a HDAC inhibitor.
- Compound 10 is administered in combination with a HDAC inhibitor.
- Compound 11 is administered in combination with a HDAC inhibitor.
- Compound 12 is administered in combination with a HDAC inhibitor.
- Compound 13 is administered in combination with a HDAC inhibitor.
- the HDAC inhibitor is selected from Vorinostat, Romidepsin, Panobinostat, and Belinostat.
- the HDAC inhibitor is selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, ⁇ -Alaninechlamydocin, depudecin, and CUDC-101.
- Compound 1 is administered in combination with an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, abexinostat, resminostat, givinostat, quisinostat, Psammaplin A, KD5170, ⁇ -Alaninechlamydocin, depudecin, and CUDC-101.
- HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cayl0603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin
- the compound of the present invention is administered in combination with an IMiD.
- the IMiD is thalidomide.
- the IMiD is lenalidomide.
- the IMiD is pomalidomide.
- Compound 1 is administered in combination with thalidomide.
- Compound 1 is administered in combination with lenalidomide.
- Compound 1 is administered in combination with pomalidomide.
- Compound 2 is administered in combination with an IMiD.
- Compound 3 is administered in combination with an IMiD.
- Compound 4 is administered in combination with an IMiD.
- Compound 5 is administered in combination with an IMiD.
- Compound 6 is administered in combination with an IMiD.
- Compound 7 is administered in combination with an IMiD.
- Compound 8 is administered in combination with an IMiD.
- Compound 9 is administered in combination with an IMiD.
- Compound 10 is administered in combination with an IMiD.
- Compound 11 is administered in combination with an IMiD.
- Compound 12 is administered in combination with an IMiD.
- Compound 13 is administered in combination with an IMiD.
- the IMiD is selected from pomalidomide, thalidomide, and lenalidomide.
- the IMiD is CC-90009. In certain embodiments, the IMiD is CC-99282. In certain embodiments, the IMiD is CC-92480. In certain embodiments, Compound 1 is administered in combination with CC-90009. In certain embodiments, Compound 1 is administered in combination with CC-99282. In certain embodiments, Compound 1 is administered in combination with CC-92480.
- Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 is administered in combination with an IMiD.
- the IMiD is selected from CC-90009, CC-99282, and CC-92480.
- the compound of the present invention is administered in combination with an antibody targeting CD20, CD30, or CD38.
- the targeted antibody is Rituximab.
- the targeted antibody is Daratumumab.
- the targeted antibody is Elotuzumab.
- the targeted antibody is Isatuximab.
- Compound 1 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 1 is administered in combination with Rituximab.
- Compound 1 is administered in combination with Daratumumab.
- Compound 1 is administered in combination with Elotuzumab.
- Compound 1 is administered in combination with Isatuximab.
- Compound 2 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 3 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 4 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 5 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 6 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 7 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 8 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 9 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 10 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 11 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 12 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- Compound 13 is administered in combination with an antibody targeting CD20, CD30, or CD38.
- the targeted antibody is selected from Rituximab, Daratumumab, Elotuzumab, and Isatuximab.
- the compound of the present invention is administered in combination with an antibody-drug conjugate.
- the antibody-drug conjugate is Brentuximab vedotin.
- the antibody-drug conjugate is Ibritumomab tiuxetan.
- the antibody-drug conjugate is Mogamulizumab.
- the antibody-drug conjugate is Obinutuzumab.
- the antibody-drug conjugate is Polatuzumab vedotin.
- the antibody-drug conjugate is Belantamab mafodotin (GSK2857916).
- the antibody-drug conjugate is MEDI2228. In certain embodiments, the antibody-drug conjugate is CC-99712. In certain embodiments, Compound 1 is administered in combination with an antibody-drug conjugate. In certain embodiments, Compound 1 is administered in combination with Brentuximab vedotin. In certain embodiments, Compound 1 is administered in combination with Ibritumomab tiuxetan. In certain embodiments, Compound 1 is administered in combination with Mogamulizumab. In certain embodiments, Compound 1 is administered in combination with Obinutuzumab. In certain embodiments, Compound 1 is administered in combination with Polatuzumab vedotin.
- Compound 1 is administered in combination with Belantamab mafodotin (GSK2857916). In certain embodiments, Compound 1 is administered in combination with MEDI2228. In certain embodiments, Compound 1 is administered in combination with CC-99712. In certain embodiments, Compound 1 is administered in combination with tafasitamab.
- Compound 2 is administered in combination with an antibodydrug conjugate.
- Compound 3 is administered in combination with an antibody-drug conjugate.
- Compound 4 is administered in combination with an antibody-drug conjugate.
- Compound 5 is administered in combination with an antibody-drug conjugate.
- Compound 6 is administered in combination with an antibody-drug conjugate.
- Compound 7 is administered in combination with an antibody-drug conjugate.
- Compound 8 is administered in combination with an antibody-drug conjugate.
- Compound 9 is administered in combination with an antibody-drug conjugate.
- Compound 10 is administered in combination with an antibody-drug conjugate.
- Compound 11 is administered in combination with an antibody-drug conjugate.
- Compound 12 is administered in combination with an antibody-drug conjugate.
- Compound 13 is administered in combination with an antibody-drug conjugate.
- the antibody-drug conjugate is selected from Brentuximab vedotin, Ibritumomab tiuxetan, Mogamulizumab, Obinutuzumab, Polatuzumab vedotin, Belantamab mafodotin (GSK2857916), MEDI2228, and CC-99712.
- the compound of the present invention is administered in combination with a bispecific antibody.
- the bispecific antibody is PF- 06863135.
- the bispecific antibody is TNB-383B.
- the bispecific antibody is REGN5458.
- the bispecific antibody is JNJ- 64007957.
- Compound 1 is administered in combination with a bispecific antibody.
- Compound 1 is administered in combination with PF-06863135.
- Compound 1 is administered in combination with TNB-383B.
- Compound 1 is administered in combination with REGN5458.
- Compound 1 is administered in combination with JNJ-64007957.
- Compound 2 is administered in combination with a bispecific antibody.
- Compound 3 is administered in combination with a bispecific antibody.
- Compound 4 is administered in combination with a bispecific antibody.
- Compound 5 is administered in combination with a bispecific antibody.
- Compound 6 is administered in combination with a bispecific antibody.
- Compound 7 is administered in combination with a bispecific antibody.
- Compound 8 is administered in combination with a bispecific antibody.
- Compound 9 is administered in combination with a bispecific antibody.
- Compound 10 is administered in combination with a bispecific antibody.
- Compound 11 is administered in combination with a bispecific antibody.
- Compound 12 is administered in combination with a bispecific antibody.
- Compound 13 is administered in combination with a bispecific antibody.
- the bispecific antibody is selected from PF-06863135, TNB- 383B, REGN5458, and JNJ-64007957.
- the compound of the present invention is administered in combination with a naked monoclonal antibody (mAb).
- the naked mAb is SEA-BCMA.
- Compound 1 is administered in combination with a naked mAb.
- Compound 1 is administered in combination with SEA-BCMA.
- Compound 2 is administered in combination with a naked mAb.
- Compound 3 is administered in combination with a naked mAb.
- Compound 4 is administered in combination with a naked mAb.
- Compound 5 is administered in combination with a naked mAb.
- Compound 6 is administered in combination with a naked mAb.
- Compound 7 is administered in combination with a naked mAb.
- Compound 8 is administered in combination with a naked mAb.
- Compound 9 is administered in combination with a naked mAb.
- Compound 10 is administered in combination with a naked mAb.
- Compound 11 is administered in combination with a naked mAb.
- Compound 12 is administered in combination with a naked mAb.
- Compound 13 is administered in combination with a naked mAb.
- the naked mAb is SEA-BCMA.
- CD38 antibodies include felzartamab, GBR 1342, TAK-573, CID-103, OKTIO, STI-6129, SGX301, and mezagitamab.
- Compound 1 is administered in combination with a CD38 antibody selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- CAR T-cell therapy selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.
- the compound of the present invention is administered in combination with a CAR T-cell therapy.
- the CAR T-cell therapy is Axicabtagene ciloleucel.
- the CAR T-cell therapy is Tisagenlecleucel.
- the CAR T-cell therapy is Idecabtagene vicleucel (ide-cel; bb2121).
- the CAR T-cell therapy is LCAR-B38M (JNJ-4528; JNJ-68284528).
- the CAR T-cell therapy is P-BCMA-101.
- the CAR T-cell therapy is PBCAR269A.
- the CAR T-cell therapy is bb21217. In certain embodiments, the CAR T-cell therapy is JCARK125 (orva-cel; orvacabtagene autoleucel). In certain embodiments, the CAR T-cell therapy is ALLO-715. In certain embodiments, the CAR T-cell therapy is Descartes-08. In certain embodiments, the CAR T-cell therapy is FCARH143. In certain embodiments, the CAR T-cell therapy is CT053.
- Compound 1 is administered in combination with a CAR T-cell therapy. In certain embodiments, Compound 1 is administered in combination with Axicabtagene ciloleucel. In certain embodiments, Compound 1 is administered in combination with Tisagenlecleucel. In certain embodiments, Compound 1 is administered in combination with Idecabtagene vicleucel (ide-cel; bb2121). In certain embodiments, Compound 1 is administered in combination with LCAR-B38M (JNJ-4528; JNJ-68284528). In certain embodiments, Compound 1 is administered in combination with P-BCMA-101. In certain embodiments, Compound 1 is administered in combination with PBCAR269A.
- Compound 1 is administered in combination with bb21217. In certain embodiments, Compound 1 is administered in combination with JCARK125 (orva-cel; orvacabtagene autoleucel). In certain embodiments, Compound 1 is administered in combination with ALLO-715. In certain embodiments, Compound 1 is administered in combination with Descartes-08. In certain embodiments, Compound 1 is administered in combination with FCARH143. In certain embodiments, Compound 1 is administered in combination with CT053.
- Compound 2 is administered in combination with CAR T-cell therapy.
- Compound 3 is administered in combination with CAR T-cell therapy.
- Compound 4 is administered in combination with CAR T-cell therapy.
- Compound 5 is administered in combination with CAR T-cell therapy.
- Compound 6 is administered in combination with CAR T-cell therapy.
- Compound 7 is administered in combination with CAR T-cell therapy.
- Compound 8 is administered in combination with CAR T-cell therapy.
- Compound 9 is administered in combination with CAR T-cell therapy.
- Compound 10 is administered in combination with CAR T-cell therapy.
- Compound 11 is administered in combination with CAR T-cell therapy.
- Compound 12 is administered in combination with CAR T-cell therapy.
- Compound 13 is administered in combination with CAR T-cell therapy.
- the CAR T-cell therapy is selected from Axicabtagene ciloleucel, Tisagenlecleucel, Idecabtagene vicleucel (ide-cel; bb2121), LCAR-B38M (JNJ-4528; JNJ- 68284528), and P-BCMA-101.
- the CAR T-cell therapy is selected from PBCAR269A, bb21217, JCARK125 (orva-cel; orvacabtagene autoleucel), ALLO-715, Descartes- 08, FCARH143, and CT053.
- the CAR T-cell Therapy is selected from ALLO-715, bb21217, BCMA CAR-T, CD138 CAR-T, CD 19 CAR-T, ciltacabtagene autoleucel, CS1 (SLAMF7) CAR- T, CT053, Descartes-11, idecabtagene vicleucel, NKG2D CAR-T, orvacabtagene autoleucel, P- BCMA-101, and UCARTCS1.
- the compound of the present invention is administered in combination with a cellular therapy.
- Compound 1 is used in combination with a cellular therapy.
- Non-limiting examples of cellular therapy include allo-HSCT, allo-NKT, auto-HSCT, and auto-NKT.
- the compound of the present invention is administered in combination with a bi-specific T-cell engagers (BiTEs).
- the BiTE is Blinatumomab.
- the BiTE is CC-93268.
- the BiTE is AMG 420.
- the BiTE is AMG 701.
- Compound 1 is administered in combination with a bi-specific T-cell engagers (BiTEs).
- Compound 1 is administered in combination with Blinatumomab.
- Compound 1 is administered in combination with AMG 420.
- Compound 1 is administered in combination with CC-93269.
- Compound 1 is administered in combination with AMG 701.
- Compound 2 is administered in combination with a BiTE.
- Compound 3 is administered in combination with a BiTE.
- Compound 4 is administered in combination with a BiTE.
- Compound 5 is administered in combination with a BiTE.
- Compound 6 is administered in combination with a BiTE.
- Compound 7 is administered in combination with a BiTE.
- Compound 8 is administered in combination with a BiTE.
- Compound 9 is administered in combination with a BiTE.
- Compound 10 is administered in combination with a BiTE.
- Compound 11 is administered in combination with a BiTE.
- Compound 12 is administered in combination with a BiTE.
- Compound 13 is administered in combination with a BiTE.
- the BiTE is selected from Blinatumomab, AMG 420, CC-93269, and AMG 4701.
- Compound 1 is used in combination with a bispecific antibody selected from AMG 420, AMG 701, BFCR4350A, blinatumomab, CC-93269, elranatamab, EM801, REGN5458, talquetamab, teclistamab, and TNB-383B.
- a bispecific antibody selected from AMG 420, AMG 701, BFCR4350A, blinatumomab, CC-93269, elranatamab, EM801, REGN5458, talquetamab, teclistamab, and TNB-383B.
- the compound of the present invention is administered in combination with a checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with a PD- 1 checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is Nivolumab. In certain embodiments, the checkpoint inhibitor is Pembrolizumab. In certain embodiments, the checkpoint inhibitor is Interferon alfa-2b. In certain embodiments, Compound 1 is administered in combination with a checkpoint inhibitor. In certain embodiments, Compound 1 is administered in combination with a PD-1 checkpoint inhibitor.
- Compound 1 is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, Compound 1 is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, Compound 1 is administered in combination with Nivolumab. In certain embodiments, Compound 1 is administered in combination with Pembrolizumab. In certain embodiments, Compound 1 is administered in combination with Interferon alfa-2b.
- Compound 2 is administered in combination with a checkpoint inhibitor.
- Compound 3 is administered in combination with a checkpoint inhibitor.
- Compound 4 is administered in combination with a checkpoint inhibitor.
- Compound 5 is administered in combination with a checkpoint inhibitor.
- Compound 6 is administered in combination with a checkpoint inhibitor.
- Compound 7 is administered in combination with a checkpoint inhibitor.
- Compound 8 is administered in combination with a checkpoint inhibitor.
- Compound 9 is administered in combination with a checkpoint inhibitor.
- Compound 10 is administered in combination with a checkpoint inhibitor.
- Compound 11 is administered in combination with a checkpoint inhibitor.
- Compound 12 is administered in combination with a checkpoint inhibitor.
- Compound 13 is administered in combination with a checkpoint inhibitor.
- the checkpoint inhibitor is a PD-1 checkpoint inhibitor.
- the checkpoint inhibitor is a PD-L1 checkpoint inhibitor.
- the checkpoint inhibitor is an IFNAR checkpoint inhibitor.
- the checkpoint inhibitor is selected from Nivolumab, Pembrolizumab, and Interferon alfa-2b.
- PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medlmmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).
- CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and AGEN2041 (Agenus).
- LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).
- BMS-986016 Bristol-Myers Squibb
- GSK2831781 GaxoSmithKline
- IMP321 Primary BioMed
- LAG525 Novartis
- MGD013 Non-Genics
- An example of a TIM-3 inhibitor is TSR- 022 (Tesaro).
- the checkpoint inhibitor is selected from nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; and pidilizumab/CT-011, MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2/lg fusion protein such as AMP 224 or an inhibitor of B7- H3 (e g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD 160, CGEN- 15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.
- B7- H3 e g., MGA271
- B7-H4 BTLA
- HVEM TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD 160, CGEN- 15049, CHK 1, CHK2, A2aR, B-7
- the PD-1 inhibitor is BGB-A317.
- the PD-L1 inhibitor is MED14736.
- the PD-L2 inhibitor is rHIgM12B7A.
- the checkpoint inhibitor is a B7 inhibitor, for example a B7-H3 inhibitor or a B7-H4 inhibitor.
- the B7-H3 inhibitor is MGA271.
- the checkpoint inhibitor is an 0X40 agonist. In certain embodiments, the checkpoint inhibitor is an anti-OX40 antibody, for example anti-OX-40 or MEDI6469.
- the checkpoint inhibitor is a GITR agonist.
- the GITR agonist is an anti-GITR antibody, for example TRX518.
- the checkpoint inhibitor is a CD137 agonist.
- the CD137 agonist is an anti-CD137 antibody, for example PF-05082566.
- the checkpoint inhibitor is a CD40 agonist.
- the CD40 agonist is an anti-CD40 antibody, for example CF-870,893.
- the checkpoint inhibitor is an IDO inhibitor, for example INCB24360 or indoximod.
- the checkpoint inhibitor is selected from atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.
- an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
- an androgen such as testosterone
- the prostate or testicular cancer is androgen-resistant.
- Non-limiting examples of anti -androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112.
- anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
- the bioactive agent is an ALK inhibitor.
- ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.
- the bioactive agent is an EGFR inhibitor.
- EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO- 1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), soloartinib (EGF816), PF- 06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD- 019), transtinib, WZ-3146, WZ8040, CNX-2006
- the bioactive agent is an HER-2 inhibitor.
- HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.
- the bioactive agent is a CD20 inhibitor.
- CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.
- the bioactive agent is a JAK3 inhibitor.
- JAK3 inhibitors include tasocitinib.
- the bioactive agent is a JAK inhibitor, for example ruxolitinib.
- the bioactive agent is a BCL-2 inhibitor.
- BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-l-en- l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l- phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl] sulfony
- the bioactive agent is venetoclax.
- the bioactive agent is a MEK inhibitor.
- MEK inhibitors are well known, and include, for example, trametinib/GSK1120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2 -hydroxy ethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonico
- the bioactive agent is a Raf inhibitor.
- Raf inhibitors include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3- yl]carbonyl]-2,4-difluorophenyl]-l -propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- m ethylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-
- the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, andKW-2449, or a combination thereof.
- AKT inhibitor including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine
- a FLT-3 inhibitor including but not limited to, P406, Dovitinib, Quizartinib (AC2
- the bioactive agent is an mTOR inhibitor.
- mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.
- MEK inhibitors include but are not limited to tametinib/GSK1120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl ⁇ phenyl)acetamide), selumetinob (6-(4-bromo-2-chl oroanilino)-7-fluoro-N-(2 -hydroxy ethoxy)-
- the bioactive agent is a RAS inhibitor.
- RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
- the bioactive agent is a HSP inhibitor.
- HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
- the bioactive agent is a biphosphonate.
- biphosphonates include but are not limited to clodronate, pamidronate, and zoledronic acid.
- Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON O91O.Na, AZD 6244 (ARRY- 142886), AMN-107, TKL258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK- 0457, MLN8054, PHA-739358, R-763, AT-9263, aFLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HD AC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a VEGF
- the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DMl, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Ves),
- the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent.
- Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds.
- General anti-cancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bos
- chemotherapeutic agents include but are not limited to 1 -dehydrotestosterone, 5 -fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (CC
- the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or another chemical compound useful in the treatment of cancer).
- chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
- 5 -fluorouracil 5 -fluorouracil
- chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065
- dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epi
- Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention.
- Suitable dosing regimens of combination chemotherapies are known in the ar.
- combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000).
- Additional therapeutic agents that can be administered in combination with a compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDL522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DMl, atiprimod, natalizumab, bortezomib, carfilzomib
- the additional therapy is a monoclonal antibody (MAb).
- MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system.
- bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
- VEGF vascular endothelial growth factor
- cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2).
- MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
- the bioactive agent is an immunosuppressive agent.
- the immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
- Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fmgolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
- Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g courts etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natal
- the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
- a biologic such as a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
- the biologic is an anti -angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®).
- the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer.
- Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-1- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panit
- the additional therapy is bendamustine. In certain embodiments, the additional therapy is obinutuzmab. In certain embodiments, the additional therapy is a proteasome inhibitor, for example ixazomib or oprozomib. In certain embodiments, the additional therapy is a histone deacetylase inhibitor, for example ACY241.
- the additional therapy is a BET inhibitor, for example GSK525762A, OTX015, BMS-986158, TEN- 010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFL1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2- methylisoquinolin-l(2H)-one, EPl 1313 and EPl 1336.
- BET inhibitor for example GSK525762A, OTX015, BMS-986158, TEN- 010, CPI-0610, INCB54329, BAY1238097, FT-1101,
- the additional therapy is an MCL-1 inhibitor, for example AZD5991, AMG176, MIK665, S64315, or S63845.
- the additional therapy is an LSD-1 inhibitor, for example ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-l-yl)-5- (3-fluoro-4-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof.
- the additional therapy is a CS1 antibody, for example elotuzumab.
- the additional therapy is a CD38 antibody, for example daratumumab or isatuximab.
- the additional therapy is a BCMA antibody or antibody-conjugate, for example GSK2857916 or BI 836909.
- the bioactive agent is selinexor. In certain embodiments, Compound 1 is administered in combination with selinexor. In certain embodiments, Compound 1 is administered in combination with aspirin.
- Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 is administered in combination with selinexor. In certain embodiments, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 is administered in combination with aspirin.
- a compound described herein is administered in combination with a drug selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.
- a drug selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, in
- Compound 1 is used in combination with a chemokine receptor antagonist, for example plerixafor.
- Compound 1 is used in combination with a vaccine, for example
- Compound 1 is used in combination with a chemotherapeutic agent, for example bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.
- a chemotherapeutic agent for example bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.
- Compound 1 is used in combination with a conjugated antibody, for example belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.
- a conjugated antibody for example belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.
- Compound 1 is used in combination with a phospholipid-drug conjugate, for example CLR 131.
- a compound described herein is used in combination with a chemokine receptor antagonist, for example plerixafor.
- a compound described herein is used in combination with a vaccine, for example PVX-410.
- a compound described herein is used in combination with a chemotherapeutic agent, for example bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.
- a chemotherapeutic agent for example bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.
- a compound described herein is used in combination with a conjugated antibody, for example belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.
- a conjugated antibody for example belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.
- a compound described herein is used in combination with a phospholipid-drug conjugate, for example CLR 131.
- a compound described herein is used in combination with a CHOP regimen (cyclophosphamide, vincristine, prednisone, and daunorubicin).
- Compound 1 is used in combination with a CHOP regimen (cyclophosphamide, vincristine, prednisone, and daunorubicin).
- Compound 1, rituximab, and CHOP are administered in combination.
- a compound described herein is used in combination with a CVP regimen (cyclophosphamide, vincristine, and prednisone).
- Compound 1 is used in combination with a CVP regimen (cyclophosphamide, vincristine, and prednisone).
- Compound 1, rituximab, and CVP are administered in combination.
- a compound described herein is used in combination with a romidepsin, belinostat, or brentuximab to treat cancer, for example T-NHL.
- Compound 1 is used in combination with a romidepsin, belinostat, or brentuximab to treat cancer, for example T-NHL.
- a compound described herein is used in combination with a polatuzumab, tafastamab, CAR-T, a BTK inhibitor, or a PI3Kinase inhibitor to treat cancer, for example B-NHL.
- Compound 1 is used in combination with a polatuzumab, tafastamab, CAR-T, a BTK inhibitor, or a PI3Kinase inhibitor to treat cancer, for example B-NHL
- Compound 1 is used in the treatment of relapsed and/or refractory mantle cell leukemia.
- Compound 1 and rituximab are used in the treatment of relapsed and/or refractory mantle cell leukemia.
- Compound 1, rituximab, and bendamustine are used in the treatment of relapsed and/or refractory mantle cell leukemia.
- Compound 1, rituximab, and ibrutinib are used in the treatment of relapsed and/or refractory mantle cell leukemia.
- Compound 1 is used in the treatment of relapsed and/or refractory marginal zone leukemia. In certain embodiments Compound 1 and rituximab are used in the treatment of relapsed and/or refractory marginal zone leukemia. In certain embodiments Compound 1, rituximab, and dexamethasone are used in the treatment of relapsed and/or refractory marginal zone leukemia.
- Compound 1 is used in combination with rituximab and DHAP (dexamethasone, cytarabine, and cisplatin). In certain embodiments Compound 1 is used in combination with DHAP (dexamethasone, cytarabine, and cisplatin). In certain embodiments Compound 1 is used in combination with rituximab and ICE (ifosfamide, carboplatin, and etoposide). In certain embodiments Compound 1 is used in combination with ICE (ifosfamide, carboplatin, and etoposide). In certain embodiments Compound 1 is used in combination with rituximab and GemOx (gemcitabine and oxaliplatin).
- Compound 1 is used in combination with GemOx (gemcitabine and oxaliplatin). In certain embodiments Compound 1 is used in combination with polatuzumab and brentuximab. In certain embodiments Compound 1 is used in combination with polatuzumab. In certain embodiments Compound 1 is used in combination with tafasitimab. In certain embodiments Compound 1 is used in combination with tafasitimab and lenolidomide. In certain embodiments Compound 1 is used in combination with rituximab and lenolidomide.
- Compound 1 is used in combination with anti CD 19 CART (for example axicabtagene, lisocabtagene, tisafenlucleucel, loncastuximab, or tesirine). In certain embodiments one of the above combinations is used in the treatment of DLBCL or B-NHL. In certain embodiments Compound 1 is used in combination with praltrexate. In certain embodiments Compound 1 is used in combination with bendamustine. In certain embodiments Compound 1 is used in combination with brexucabtagene. In certain embodiments Compound 1 is used in combination with bortezomib and rituximab. In certain embodiments Compound 1 is used in combination with bendamustine and rituximab. In certain embodiments Compound 1 is used in combination with VR-CAP (rituximab, cyclophosphamide, doxorubicin, prednisone, and bortzomib).
- anti CD 19 CART for example axicabtagen
- Compound 1 is used in combination with carfilzomib and daratumumab. In certain embodiments Compound 1 is used in combination with abecma. In certain embodiments Compound 1 is used in combination with melflufen. In certain embodiments Compound 1 is used in combination with ciltacabtagene autoleucel.
- compositions for example Compound 1 are used in a therapy in the table below. In other embodiments Compound 1 is replaced with a different compound described herein.
- any of the compounds as disclosed herein can be administered as the neat chemical, but are more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein.
- the pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent.
- the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 50 mg to about 600 mg, or from about 100 mg to about 400 mg of the active compound.
- the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 100 mg, from about 0.5 mg to about 100 mg, from about 1 mg to about 50 mg, or from about 2 mg to about 25 mg of the active compound.
- the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 10 mg, from about 0.5 mg to about 8 mg, from about 0.5 mg to about 6 mg, or from about 0.5 mg to about 5 mg of the active compound. Examples are dosage forms with at least, or in some embodiments, not more than, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
- the pharmaceutical composition is in a dosage form that contains from about 1 ⁇ g to about 2000 ⁇ g, from about 10 ⁇ g to about 1000 ⁇ g, from about 50 ⁇ g to about 600 ⁇ g, or from about 100 ⁇ g to about 400 ⁇ g of the active compound.
- the pharmaceutical composition is in a dosage form that contains from about 1 ⁇ g to about 400 ⁇ g, from about 5 ⁇ g to about 400 ⁇ g, from about 10 mg to about 250 ⁇ g, or from about 25 ⁇ g to about 250 ⁇ g of the active compound. Examples are dosage forms with at least, or in some embodiments, not more than, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 ⁇ g of active compound, or its salt.
- the pharmaceutical composition may also include a molar ratio of the active compound and an additional bioactive agent.
- the pharmaceutical composition may contain a molar ratio of about 0.0005: 1, about 0.001 : 1, about 0.01 : 1, about 0.05: 1, or about 0.1 : 1 of active compound to an anti-inflammatory or immunosuppressing agent.
- the pharmaceutical composition may contain a molar ratio of about 0.5: 1, about 1 : 1, about 2: l, about 3: l or from about 1.5:1 to about 4: 1 of active compound to an anti-inflammatory or immunosuppressing agent.
- Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intravenous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
- the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
- the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution.
- Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
- Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
- the carrier can be inert or it can possess pharmaceutical benefits of its own.
- the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
- Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
- Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
- Pharmaceutically acceptable carriers are carriers that do not cause any severe adverse reactions in the human body when dosed in the amount that would be used in the corresponding pharmaceutical composition.
- Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
- Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
- compositions/combinations can be formulated for oral administration.
- These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 wt.% of the compound.
- Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound.
- Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- conventional solid carriers for example, cocoa butter
- Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
- Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
- Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
- microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
- Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
- DPI dry powder inhalers
- the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
- nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
- a compound described herein for example Compound 1, is formulated as described in Table A.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising Compound 1, a nonaqueous solvent, a preservative, and/or a pH control agent.
- a compound described herein for example Compound 1
- Non-limiting examples of preservatives include alcohols (for example, ethanol, benzyl alcohol), aluminum acetate, benzalkonium chloride, benzethonium chloride, benzoic acid and salts thereof (for example, potassium benzoate, sodium benzoate), boric acid and salts thereof (for example, sodium borate), bronopol, butylene glycol, butylated hydroxyanisole, calcium acetate, calcium chloride, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, edetic acid and salts thereof, gelatin, glycerin, hexetidine, imidurea, lactic acid and salts thereof (for example, calcium lactate, sodium lactate), monothioglycerol, parabens (for example, butylparaben, ethylparaben methylparaben, propylparaben, propylparaben sodium
- pH control agent can be used interchangeably with pH adjustment agent, pH regulator, and/or buffering agent.
- pH control agents include acetic acid, glacial acetic acid, adipic acid, strong ammonia solution and salts thereof (for example, ammonium carbonate, ammonium chloride, ammonium phosphate), arginine, boric acid and salts thereof (for example, sodium borate), calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, citric acid (anhydrous or monohydrate) and salts thereof (for example, potassium citrate, sodium citrate), diethanolamine, fumaric acid and salts thereof, glycine, gluconic acid, hydrochloric acid, diluted hydrochloric acid, alpha-lactalbumin, lactic acid and salts thereof (for example, sodium lactate solution), lysine hydrochloride, maleic acid, malic acid, methionine, monoethanolamine, monosodium glutamate, meglumine, n
- Non-limiting examples of buffering agents include, but are not limited to, adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, citric acid, sodium phosphate, diethanolamine, maleic acid, malic acid, methionine, monoethanolamine, sodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide, sodium lactate and triethanolamine.
- the buffering agent is selected from carbonates, citrates, gluconates, lactates, phosphates, tartrates, potassium metaphosphate, potassium phosphate, monobasic, sodium acetate, sodium citrate, anhydrous and dihydrate.
- the pharmaceutical composition includes water.
- the pharmaceutical composition includes a non-aqueous or anhydrous solvent.
- Nonlimiting examples of non-aqueous solvents include alcohols (for example, ethanol), PEG 300, PEG 400, propylene glycol, cremophor, caplex 355, CapryolTM 90, LauroglycolTM 90, TranscutolHP, butylated hydroxytoluene, benzyl alcohol, citric acid, triacetin, propylene glycol, fats and oils.
- Table B 25 ⁇ g strength formulation
- Compound 1 is provided in a liquid filled capsule comprising a solvent, preservative, and pH control agent.
- composition of any one of embodiments 1-13 wherein the capsule is filled with a solution comprising about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 065, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, 2.75, or 3% pH control agent by weight.
- a compound described herein is administered as a pharmaceutical composition comprising one or more excipients from the Handbook of Pharmaceutical Excipients 9 th Edition (or earlier).
- a compound described herein is dissolved or dispersed in oil or fat components.
- the oil or fat component may form a micro-emulsion in the digestive system so that the compound is more quickly absorbed in the body.
- the oil is an edible oil, a medicament oil, a pharmaceutically acceptable fat and oil, or a food-acceptable fats and oil.
- the pharmaceutically acceptable fat and oil, or a food-acceptable fats and oil includes, but is not limited, to a vegetable oil, an animal oil, a fish oil or a mineral oil.
- the edible oil is selected from the group consisting of medium chain fatty acid triglyceride, amaranth oil, apricot oil, apple oil, argan oil, artichokes oil, avocado oil, almond oil, acai berry extract, arachis oil, buffalo pumpkin oil, borage seed oil, borage oil, babassu oil, coconut oil, com oil, cottonseed oil (cotton seed oil), cashew oil, carob oil, Coriander oil, camellia oil (Camellia oil), Cauliflower oil, cape chestnut oil, cassis oil, deer oil, evening primrose oil, grape syrup Oila oil (hibiscus oil), grape seed oil, gourd oil, hazelnut oil, hemp oil, kapok oil, krill oil, linseed oil, macadamia nut oil, Mongolia oil, moringa oil, malula oil, meadowfoam oil, mustard oil, niger seed oil, olive oil, okrao oil Hibiscus
- the fat-soluble oil is a vitamin including, but is not limited, to vitamin A oil, vitamin D oil, vitamin E oil, vitamin K oil, and derivatives thereof; and glycerophospholipids such as lecithin, and any combination thereof; can also be used as fats and oils in the present invention.
- the oil in the present invention may be a liquid (such as a fat oil) or a solid (a fat or the like) at room temperature.
- the oil in the present invention is a liquid at the temperature in the living body (in particular, the temperature of the stomach, around 37 ° C ).
- the fat includes many saturated fatty acids (for example, palmitic acid, stearic acid), and/or fatty oils contain many unsaturated fatty acids (for example, oleic acid, linoleic acid, linolenic acid); and wherein these fatty acids and oils may be esterified.
- the fatty acids having 2 to 4 carbon atoms are called short chain fatty acids (lower fatty acids), 5 to 12 fatty acids as medium chain fatty acids, and fatty acids with 12 or more carbon atoms as long chain fatty acids (higher fatty acids). Since fatty acids generally have a high hydrophilicity when the number of carbon atoms is small, oils of the present invention include medium chain fatty acids (for example, medium chain fatty acid triglycerides such as tri (caprylic / capric acid) glycerol and glyceryl tricaprylate) and long Chain fatty acid.
- medium chain fatty acids for example, medium chain fatty acid triglycerides such as tri (caprylic / capric acid) glycerol and glyceryl tricaprylate
- long Chain fatty acid for example, medium chain fatty acid triglycerides such as tri (caprylic / capric acid) glycerol and glyceryl tricaprylate
- the fatty acid is used in combination with a saturated polyglycolated glyceride obtained by polyglycolysis of hydrogenated vegetable oil with polyethylene glycol, a mono-, di- or triglyceride, and a mono- or di-fatty acid ester of polyethylene glycol.
- the pharmaceutical composition includes a diluent.
- diluent used in capsules include, but are not limited to, calcium carbonate, calcium phosphate di or tri basic, kaolin, lactose, lactitol, mannitol, microcrystalline cellulose, powdered cellulose, cellulose acetate, sorbitol, starch, calcium sulfate, dextrates, dextrin, dextrose, maltodextrin, erythritol, glyceryl palmitostearate, isomalt, magnesium carbonate, magnesium oxide, mannitol, sodium chloride, sucrose, sulfobutylether b-cyclodextrin, talc, and xylitol.
- a metabolite of Compound 1 is used as either
- the metabolite of Compound 1 is enantiomerically or diasteromerically enriched:
- a Compound 1 metabolite is used in a treatment described herein.
- a Compound 1 metabolite is used as an intermediate in the preparation of Compound 1.
- the compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below.
- This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e.
- the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers.
- kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC).
- the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is place in contact with a thin membrane barrier.
- the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; xiv) simulated moving bed chromatography is used in one embodiment.
- a wide variety of chiral stationary phases are commercially available.
- Step 1 Synthesis of 6-bromo-lH-benzo[cd]indol-2-one (2): A solution of molecular bromine (354.23 g, 2.22 mol, 113.53 mL) in chloroform (500 mL) was added drop wise at 0°C to a stirred suspension of lH-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) in chloroform (2.5 L), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mass was poured into a saturated solution of sodium thiosulphate in water.
- Step 2 Synthesis of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[cd]indol-2- one (3): Bis(pinacolato) diboron (30.71 g, 120.93 mmol) followed by well dried potassium acetate (23.74 g, 241.86 mmol, 15.12 mL) was added to a stirred solution of 6-bromo-lH-benzo[cd]indol- 2-one (2) (20 g, 80.62 mmol) in 1,4 dioxane (500 mL). The resultant reaction mass was degassed well with argon for 15 minutes.
- Step 3 Synthesis of 4-(4-(chloromethyl)benzyl)morpholine (6): To a stirred solution of morpholine (5) (8 g, 91.83 mmol, 8.03 mL) in analytical grade acetone (15 mL) was added 99% potassium carbonate, anhydrous, (12.69 g, 91.83 mmol, 5.54 mL) at room temperature and the resultant reaction mixture was heated at 50°C for 20 minutes. l,4-bis(chloromethyl)benzene (4) (16.07 g, 91.83 mmol, 11.32 mL) was then added to the reaction mixture and heating was continued for 3 hours.
- Step 4 Synthesis of 6-(4-(morpholinomethyl)benzyl)benzo[cd]indol-2(lH)-one (7): To a well degassed solution of 4-[[4-(chloromethyl)phenyl]methyl]morpholine (6) (8 g, 35.44 mmol) and 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[cd]indol-2-one (3) (20.92 g, 70.89 mmol) in a mixture of ethanol (20 mL) and toluene (40 mL), was added anhydrous tribasic potassium phosphate (22.57 g, 106.33 mmol) followed by the addition of tri-o-tolyl phosphine (2.16 g, 7.09 mmol) and Pd 2 (dba) 3 (3.25 g, 3.54 mmol).
- the resulting mixture was then heated at 90°C for 12 hours. After completion of the reaction (as monitored by LCMS), the reaction mixture was filtered through a bed of celite and washed with ethyl acetate (200 mL). The combined filtrate was then washed with water (3 x 50 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step 5 Synthesis of 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione: To an ice cooled solution of 6-[[4-(morpholinomethyl)phenyl]methyl]- lH-benzo[cd]indol-2-one (7) (4.8 g, 13.39 mmol) in dry THF (50 mL), sodium hydride (60% dispersion in mineral oil) (3.08 g, 133.92 mmol) was added portion wise, maintaining the temperature at ⁇ 5°C. Once the addition was complete, the resultant mixture was stirred for 15 minutes at room temperature.
- reaction mixture was again cooled to 0°C and 3- bromopiperidine-2, 6-dione (8) (12.86 g, 66.96 mmol) was added to it portion wise. After complete addition, the resulting solution was heated at 70°C for 1 hour. After completion (evidenced from TLC), the reaction mixture was again cooled to 0°C and quenched with ice cooled water (40 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). Combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step 6 Chiral separation: Preparation of R- and S-3-(6-(4-(morpholinomethyl)benzyl)-2- oxobenzo[cd]indol-l(2H)-yl)piperidine-2, 6-dione: 3.8 g of 3-(6-(4-(morpholinomethyl)benzyl)- 2-oxobenzo[cd]indol-l(2H)-yl)piperidine-2, 6-dione Compound 5 was separated into enantiomers by the chiral normal phase preparative HPLC method below. The fractions were first evaporated separately under reduced pressure to obtain a solid mass.
- Mobile phase 500 mL of DCM and 500 mL of isopropyl alcohol were mixed and sonicated to degas.
- Step 1 Synthesis of l-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (3): To a stirred solution of l-(2-fluorophenyl)piperazine (1) (2 g, 11.10 mmol) in dry grade DMF (5 mL), DIPEA (4.30 g, 33.29 mmol, 5.80 mL) was added followed by l,4-bis(chloromethyl)benzene (2) (3.89 g, 22.19 mmol, 2.74 mL). The resulting reaction mixture was heated at 60°C for 12 hours.
- Step 2 Synthesis of 6-[[4-[[4-(2-fluorophenyl)piperazin-l-yl]methyl]phenyl]methyl]-lH- benzo[cd]indol-2-one (5): To the stirred solution of 6-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)- lH-benzo[cd]indol-2-one (4) (500 mg, 1.68 mmol) and l-[[4-(chloromethyl)phenyl]methyl]-4-(2- fluorophenyl)piperazine (3) (536.10 mg, 1.68 mmol) in ethanol (1 mL) and toluene (2 mL) was added tripotassium phosphate (892.33 mg, 4.20 mmol) followed by 0.5 ml water and the reaction mass was degassed under nitrogen atmosphere over 10 minutes.
- Step 3 Preparation of 3-[6-[[4-[[4-(2-fluorophenyl)piperazin-l-yl]methyl]phenyl]methyl]-2- oxo-benzo[cd]indol-l-yl]piperidine-2, 6-dione: To an ice cooled solution of 6-[[4-[[4-(2- fluorophenyl)piperazin-l-yl]methyl]phenyl]methyl]-lH-benzo[cd]indol-2-one 5 (80 mg, 177.17 umol) in dry THF (8 mL), sodium hydride (in oil dispersion) 60% dispersion in mineral oil (67.89 mg, 1.77 mmol, 60% purity) was added portion wise, while the temperature was maintained at ⁇ 5°C.
- Step-1 Synthesis of tert-butyl 4-(4-cyano-2-fluoro-phenyl)piperazine-l-carboxylate (3): To a stirred solution of 3,4-difluorobenzonitrile (1) (13 g, 93.46 mmol) in DMSO (80 mL), potassium carbonate (19.37 g, 140.18 mmol, 8.46 mL) and tert-butyl piperazine- 1 -carboxylate (2) (19.15 g, 102.80 mmol) were added and the resulting reaction mixture was heated at 100°C for 16 hours. After completion (monitored by TLC), the reaction mixture was allowed to cool and water (500 ml) was added to it.
- Step-2 Synthesis of 3-fluoro-4-piperazin-l-yl-benzonitrile Hydrochloride salt (4): To a stirred solution of tert-butyl 4-(4-cyano-2-fluoro-phenyl)piperazine-l -carboxylate (3) (20 g, 65.50 mmol) in dioxane (15 mL) was added dioxane-HCl (65.50 mmol, 50 mL) and the reaction mixture was stirred at room temperature for 3 hours. All the volatiles were removed under reduced pressure. The solid obtained was triturated with ether to afford 3-fluoro-4-piperazin-l-yl- benzonitrile; hydrochloride (4) (17 g, 88% yield) as a white solid.
- LC MS ES+ 206.4.
- Step-3 Synthesis of 4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-l-yl]-3-fluoro- benzonitrile (6): To a stirred solution of 3-fluoro-4-piperazin-l-yl-benzonitrile; hydrochloride (4) (15 g, 62.06 mmol) in DMF (75 mL) was added DIPEA (24.06 g, 186.19 mmol, 32.43 mL) and the reaction mixture was stirred for 5 minutes.
- Step-4 Synthesis of 3-fluoro-4-[4-[[4-[(2-oxo-lH-benzo[cd]indol-6- yl)methyl]phenyl]methyl]piperazin-l-yl]benzonitrile (7): To a well degassed solution of 4-[4- [[4-(chloromethyl)phenyl]methyl]piperazin-l-yl]-3-fluoro-benzonitrile (6) (7 g, 20.36 mmol) and 6-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)-lH-benzo[cd]indol-2-one (3) (9.08 g, 30.54 mmol) in ethanol (30 mL) and toluene (60 mL), anhydrous potassium phosphate tribasic, (10.80 g, 50.90 mmol) was added followed by the addition of tri-o-tolyl phosphine (1.24
- reaction mixture was then heated at 100°C for 16 hours. After completion of reaction (as monitored by LCMS), the reaction mixture was filtered through a bed of celite, and washed with ethyl acetate. The combined filtrate was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure.
- Step-5 Synthesis of 4-[4-[[4-[[l-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6 yl ] methyl] phenyl] methyl] piperazin-l-yl] -3-fluoro-benzonitrile: To a cooled solution of fluoro-4-[4-[[4- [(2-oxo-lH-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-l-yl]benzonitrile (7) (5.5 g, 11.54 mmol) in dry THF (30 mL), sodium hydride (60% dispersion in mineral oil) (2.65 g, 115.41 mmol) was added portion wise, maintaining the temperature at ⁇ 5°C.
- the resultant mixture was stirred for 15 minutes at room temperature. Then the reaction mixture was again cooled to 0°C and 3 -brom opiperidine-2, 6-dione (8) (11.08 g, 57.71 mmol) was added to it portion wise. After complete addition, the resulting solution was heated at 70°C 1 hour. After completion (evidenced from TLC), the reaction mixture was cooled to 0°C and quenched with the addition of ice cooled water. The aqueous layer was extracted with ethyl acetate (3 x lOOmL). The combined organics were separated, dried over sodium sulfate, and concentrated under reduced pressure.
- Step 1 Synthesis of 6-bromo-lH-benzo[cd]indol-2-one (2): To a stirred suspension of 1H- benzo[cd]indol-2-one (1) (250 g, 1.48 mol) in chloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol, 113.53 mL) in chloroform (500 mL) was added drop wise at 0°C and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mass was poured into a saturated solution of sodium thiosulphate in water.
- Step 2 Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2- one: To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (100 g, 403.10 mmol) in 1,4- dioxane (1 L) was added bis(pinacolato)diboron (153.55 g, 604.66 mmol) followed by well dried potassium acetate (118.68 g, 1.21 mol, 75.60 mL). The resultant reaction mass was degassed well with argon for 15 minutes.
- Step 3 Synthesis of 8-(4-(chloromethyl)benzyl)-1-oxa-8-azaspiro[4.5]decane (6): To a stirred solution of 1-oxa-8-azaspiro[4.5]decane;hydrochloride (5) (5 g, 28.14 mmol) in dry grade acetone (50 mL) was added DIPEA (3.64 g, 28.14 mmol, 4.90 mL) followed by 99% anhydrous potassium carbonate (11.67 g, 84.43 mmol, 5.10 mL) at room temperature and the resulting reaction mixture was heated at 50°C for 20 minutes.
- DIPEA 3.64 g, 28.14 mmol, 4.90 mL
- anhydrous potassium carbonate 11.67 g, 84.43 mmol, 5.10 mL
- 1,4-bis(chloromethyl)benzene (4) (9.85 g, 56.28 mmol, 6.94 mL) was then added to the reaction mixture and heating was continued for 3 hours. After completion of the reaction (monitored by TLC and LCMS), volatiles were removed under vacuum and the solid thus obtained was taken in ethyl acetate (20 mL), washed with water and brine (x3), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step 4 Synthesis of 6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)benzo[cd]indol- 2(1H)-one (8): To a well degassed solution of 8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8- azaspiro[4.5]decane (6) (4.68 g, 16.73 mmol) and 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-1H-benzo[cd]indol-2-one (7) (9.87 g, 33.45 mmol) in ethanol (20.0 mL) - Toluene (40.0 mL), Potassium phosphate tribasic anhydrous (10.65 g, 50.18 mmol) was added followed by the addition Tri-o-Tolyl phosphine (1.02 g, 3.35 m
- Step 5 Synthesis of 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2- oxobenzo[cd]indol-l(2H)-yl)piperidine-2, 6-dione: To a ice cooled solution of 6-[[4-(1-oxa-8- azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-lH-benzo[cd]indol-2-one (8) (2.83 g, 6.86 mmol) in dry THF (20 mL), sodium hydride (60% dispersion in mineral oil) (2.63 g, 68.60 mmol, 60% purity) was added portion wise.
- Step 6 Chiral separation: 1.2 g of 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2, 6-dione was separated into enantiomers by the chiral normal phase preparative HPLC method below. The fractions were first evaporated separately under reduced pressure to obtain solid mass. The solid was then suspended in a mixture of acetonitrile and water (2:3) and it was kept in a dry-ice/acetone bath until the acetonitrile- water mixture solidified.
- Mobile phase 600 mL of DCM and 400 mL of Isopropyl alcohol were mixed and sonicated to degas.
- Biomarker assessment in MM and A LCL tumor bearing studies showed deep degradation (>75%) by Compound 1 of both IKZF1/3 with duration of 24 hours.
- Compound 1 was effective in MM animal models that were resistant to pomalidomide.
- Mice bearing RPMI-8226 human MM tumor xenografts showed no response when treated with pomalidomide (3000 ⁇ g/kg/day, clinically relevant dose) for 17 days, and once Compound 1 was administered to those animals at 100 ug/kg/day it led to rapid tumor regression.
- CBI7 SC1D mice bearing established RPMI-8226 xenografts were administered pomalidomide (3000 ug/kg/day) on a daily PO regimen for 3 weeks. Pomalidomide treatment was then stopped and mice were treated with Compound 1 (100 ⁇ g/kg/day) on a daily regimen for 2 weeks. Data are expressed as mean tumor volumes ⁇ SEM.
- IKZF 1/3 are not degraded in mouse cells treated with thalidomide or its IMiD® analogs because of a single amino acid difference in mouse cereblon compared to human cereblon that, causes steric hindrance and prevents recruitment of IKZF1/3.
- Ex vivo studies were performed in peripheral blood cells (PBMC) of mice, rats, dogs, and monkeys to identify relevant species for IND enabling- toxicity studies based on the degree of IKZF1 degradation by Compound 1.
- IKZF1 was not degraded in mouse or rat cells by Compound 1, thus, while rat could not be considered a pharmacologically relevant species for human risk assessment, it was chosen as the rodent species for toxicological studies because it is widely used in toxicity testing and a substantial historical toxicology database is available.
- Compound 1 was highly effective in degrading IKZF 1/3 in cynomolgus monkey cells but had no effect on IKZF 1/3 in dog cells. Therefore, cynomolgus monkey was chosen for non-rodent toxicological studies.
- SALL4 Sal-like protein 4
- GSPT1 G1 to S Phase Transition 1
- the potency of Compound 1 was determined using an NCI-H929 viability assay and compared to pomalidomide.
- NCH4929 cell viability was determined based on quantification of ATP using CellTiter-Glo® 2.0 luminescent Assay kit, which signals the presence of metabolically- active cells. Briefly, test compound was added to 384-well plates at a top concentration of 1 ⁇ M with 10 points, half log titration in duplicates.
- NCIH929 cells were seeded into the 384-well plates in RPMI medium containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 750 cells per well.
- Cells treated in the absence of the test compound were the negative control and cells treated in the absence of CellTiter-Glo® 2.0 were the positive control.
- Cells treated with the test compounds were incubated at 37 °C with 5% CO 2 for 96 hr.
- CellTiter-Glo reagent was then added to the cells and Luminescence was acquired on EnVisionTM Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). % Viability was determined by normalizing the signal with positive and DMSO treated negative controls on the same microtiter plate. The results are shown in Figure 1 A and Table 2. As shown in Table 2, Compound 1 exhibited an IC50 of 0.071 ⁇ M.
- NCI-H929 IKZF1 degradation was also determined. Endogenous expression of IKZF1 in NCIH929 cells was determined by addition of N-terminal HiBiT tag to the NCIH929 cell line using CRISPR-Cas9. Briefly, test compound was added to 384-well plates at a top concentration of 1 ⁇ M with 10 points, half log titration in duplicates. NCIH929 cells expressing HiBiT-tagged IKZF1 were seeded into the 384-well plates in RPMI medium containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 15000 cells per well.
- the data in Figure 29 was produced by measuring IKZF1 degradation after addition of N- terminal HiBiT tag to the endogenously expressed IKZF1 in NCIH929 cell line using CRISPR- Cas9. Test compound was added to 384-well plates at a top concentration of 1 ⁇ M for Compound 1 and 10 ⁇ M for pomalidomide with 22 points, 2-fold titration in duplicates. NCIH929 cells expressing HiBiT-tagged IKZF1 were seeded into the 384-well plates in RPMI medium containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 15000 cells per well. Cells treated in the absence of the test compound were the negative control and wells containing media only were the positive control.
- HiBiT signal was determined using Nano-GioTM HiBiT Lytic Assay System (Promega, N3050) and luminescence was acquired on EnVisionTM Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). % IKZF1 remaining was determined by normalizing the signal with positive and negative controls on the same microtiter plate. Curve fit and IC50 determination was performed by 4 parametric regression analysis. Compound 1 induced rapid degradation of IKZF1, resulting in 50% degradation after 1 hour treatment and > 80% maximal degradation after 2 hour treatment with a DC50 of 21 ⁇ M. Pomalidomide degraded less than 25% of IKZF1 at 1 hour and Compound 1 showed potency > 2000-fold greater than pomalidomide at 2 hr.
- Example 10 Compound 1 Selectivity in ALCL Tumor Xenografts Using Global Proteomics
- NOD SCI mouse bearing ALCL ALK+ DL40 xenografts were treated orally with 100 ⁇ g/kg of Compound 1. After 1, 4, 24 and 48 hour treatment, biological duplicates of tumoral cells were harvested, washed twice with PBS, and snap frozen in liquid nitrogen. Samples were resuspended in lysis buffer [8 M urea, 50 mM EPPS (pH 8.5), 50 mM NaCl, lx protease inhibitor cocktail] and lysed by sonication.
- Lysates were centrifuged at maximum speed, reduced for 1 hour at room temperature with 5 mM TCEP, and the cysteine residues were then alkylated with 15 mM iodoacetamide (room temperature, in dark, 30 minutes). Protein content was extracted twice by methanol-chloroform precipitation and subsequent ice-cold acetone washes. Protein pellets were resuspended in 8 M urea, 50 mM EPPS (pH 8.5) buffer and protein concentrations were measured by BCA assay.
- peptide labeling 100 ⁇ g of peptides per sample was prepared at 1 ⁇ g/pl concentration in 200 mM EPPS (pH 8.5), ACN was added to a final concentration of 30% and then 50 ⁇ g of each TMT10 reagent. After 1 hour incubation at room temperature, reactions were quenched with 0.3% hydroxylamine for 15 minutes and mixed equally. The mixed sample was desalted using the tC18 SepPak solid-phase extraction cartridges, and lyophilized.
- Dried peptides were resuspended in 5% ACN, 10 mM NH4HCO3 pH 8 and fractionated in a basic pH reversed phase chromatography using a HPLC equipped with a 3.5 pm XB ridge Peptide BEH Cl 8 column. 96 fractions were collected, which were consolidated into 24, of which only 12 nonadj acent samples were analyzed. Samples were desalted, dried via vacuum centrifugation and reconstituted in 12pL of 5% formic for LC- MS/MS analysis.
- Ki-JK cells (DSMZ, ACC 695) were seeded in 96-well plates prespotted with Compound 1 in dose response (11 -point, duplicate, 0.001-100 nM), with and without bortezomib (proteasome inhibitor, 10 ⁇ M) or MLN-4924 (neddylation inhibitor, 10 ⁇ M). The cells were prepared for staining using the FOXP3 Fix/Perm Buffer Set (BioLegend, 421403) according to the manufacturer’s instructions at 1.5, 3, and 6 hours.
- IKZF1-AF488 (564867) and IgGl-488 (557782) (BD Biosciences) were diluted 1 : 100 in Perm Buffer. Signal was detected using the Guava® easyCyteTM Flow Cytometer. As shown in Figure 3, potent dose response degradation over time with Compound 1 was observed and the maximal degradation was observed at 6 hours. Degradation was not observed with the combination of Compound 1 and bortezomib or MLN- 4924.
- the anti -proliferative activity of Compound 1 in hematological cancer cell lines was evaluated and compared to Pomalidomide. The cells were treated for 96 hours and the results are shown in Table 5. Compound 1 is more potent than pomalidomide in every cell line, and in multiple cell lines, it is more than 5,000-fold more active. Table 5. Anti-proliferative activity of Compound 1 in Hematological Cancer Cell Lines
- Compound 1 efficacy in two multiple myeloma cell lines was evaluated at four different doses: 3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, and 100 ⁇ g/kg.
- Compound 1 was administered QD (every day) orally (PO).
- the efficacy of Compound 1 was compared to pomalidomide (administered at 3000 ⁇ g/kg).
- the results in the NCI-H929 and RPMI-8826 cells lines are shown in Figures 4 and 5, respectively.
- Table 6 describes the statistical significance of the experiment in each cell line for each dose.
- Compound 1 at all four concentrations was reduced tumor volume more than pomalidomide administered at 3000 ⁇ g/kg.
- NCI-H929 cells For the NCI-H929 cells, the xenograft study was conducted in female NOD SCID mice bearing NCI-H929 multiple myeloma tumors.
- Compound 1 was dosed at 3, 10, 30, or 100 ⁇ g/kg and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Pomalidomide was dosed at 3000 ⁇ g/kg and used the same formulation as Compound 1.
- Body weight and MTV were measured on a 2x weekly schedule and the study end point was a MTV of 2460 mm 3 in the vehicle control group on Day 18.
- Statistical analysis was performed using two-way analysis of variance (ANOVA). Data are expressed as MTV ⁇ SEM.
- the animals were divided randomly into groups of 6, stratified to result in about equal average tumor sizes in each treatment group. Treatment began on Day 0 with established subcutaneous RPMI-8226 tumors with a mean tumor volume (MTV) of 130 mm 3 .
- MTV mean tumor volume
- Compound 1 was administered at 300 ⁇ g/kg QD (every day) orally to female NOD SCID mice with disseminated MM1.S multiple myeloma tumors with a measurable MM1.S tumor burden on day 0 and dosed PO daily for 3 weeks.
- Compound 1 was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Body weight and tumor burden were measured on a 2x weekly schedule and the study end point was 20 days post the dosing, day 41. Data are expressed as mean BLI ⁇ SEM.
- IVIS Lumina II Perkin Elmer
- FIG. 1 29 days post tumor cell inoculation mice were randomized into two groups, with 3 mice per group and an average BLI of 17x10 6 photons.
- Figure 6 are images of the mice administered Compound 1 compared to the mice administered vehicle. Images were taken on days 4, 7, 11, 14, and 18. As shown in Figure 8, the total bioluminescence signal of the mice administered Compound 1 was significantly less than the mice administered vehicle. This data is also presented in Figure 34.
- Compound 1 was tested in a multiple myeloma cell line resistant to pomalidomide (H929 PomR) and a refractory multiple myeloma cell line (RPMI8226). The results are shown in Figure 8 (H929 PomR cells) and Figure 9 (RPMI-8226 cells).
- H929 multiple myeloma cells resistant to pomalidomide (H929 PomR) were generated by continued treatment in vitro with pomalidomide until the proliferation of cells was no longer inhibited.
- mice were administered Compound 1 (100 ⁇ g/kg/day) or pomalidomide (3000 ⁇ g/kg/day) on a daily PO regimen. Both compounds were formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Body weight and mean tumor volume (MTV) were measured on a 2x weekly schedule, and the study end point was a MTV of 1048 mm 3 in the pomalidomide control group on Day 24. Data are expressed as MTV ⁇ SEM. As shown in Figure 8, the tumors in the mice administered Compound 1 were smaller over the course of the study the mice administered pomalidomide.
- the animals were divided randomly into groups of 6, stratified to result in about equal average tumor sizes in each treatment group. Treatment began on Day 0 with established subcutaneous RPMI-8226 tumors with a mean tumor volume (MTV) of 130 mm 3 .
- MTV mean tumor volume
- mice bearing RPMI-8226 tumors on day 0 and dosed PO All agents were administered to mice bearing RPMI-8226 tumors on day 0 and dosed PO.
- Pomalidomide was dosed at 3000 ⁇ g/kg for 17 days and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Vehicle treated animals were treated for 28 days until tumors reached a MTV of 2211 mm 3 .
- Pomalidomide treated animals were crossed over onto Compound 1 (100 ⁇ g/kg/day) starting on day 18 and dosed for 21 additional days. Data are expressed as MTV ⁇ SEM. As shown in Figure 9, the tumor volume began to decrease when mice were crossed over from pomalidomide to Compound 1.
- the animals were divided randomly into groups of 6, stratified to result in about equal average tumor sizes in each treatment group. Treatment began on Day 0 with established subcutaneous RPMI-8226 tumors with a mean tumor volume (MTV) of 130 mm 3 .
- MTV mean tumor volume
- mice were randomized into groups of 6. Treatment began on Day 0 with established subcutaneous RPMI-8226 tumors with an MTV of 130 mm 3 . Animals were weighed on a twice weekly schedule. Mice were administered Compound (100 ⁇ g/kg/day) or pomalidomide (3000 ⁇ g/kg/day) on a daily PO regimen. Both compounds were formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Compound 1 was tested in both a mantle cell xenograft model (RECI) and a DLBLC tumor xenograft model (TMD8). The results are shown in Figure 10 (RECI) and Figure 11 (TMD8). Table 7 describes the statistical significance of the experiment in each model for each dose.
- the animals were divided randomly into groups of 6, stratified to result in about equal average tumor sizes in each treatment group. Treatment began on Day 0 with established subcutaneous RECI tumors with a mean tumor volume (MTV) of 112 mm 3 .
- MTV mean tumor volume
- mice bearing RECI tumors on day 0 and dosed PO daily for 18 days Compound 1 was dosed at 3, 10, 30, or 100 ⁇ g/kg and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Pomalidomide was dosed at 3000 ⁇ g/kg and used the same formulation as Compound 1. Body weight and MTV were measured on a 2x weekly schedule, and the study end point was a MTV of 1608 mm 3 in the vehicle control group on Day 18. Statistical analysis was performed using two-way analysis of variance (ANOVA). Data are expressed as MTV ⁇ SEM. As shown in Figure 10, tumor volume decreased in mice administered 10, 30, or 100 ⁇ g/kg of Compound 1, but increased in mice administered pomalidomide.
- Compound 1 was dosed at 100 ⁇ g/kg and Pomalidomide was dosed at 3000 ⁇ g/kg. Both compounds were formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Body weight and MTV were measured on a 2x weekly schedule and the study end point was a MTV of 2120 mm 3 in the vehicle control group on Day 18.
- Statistical analysis was performed using two-way analysis of variance (ANOVA). Data are expressed as MTV ⁇ SEM. As shown in Figure 11, tumor volume decreased in mice administered Compound 1, but increased in mice administered pomalidomide.
- Example 17 Compound 1 induces Deep and Durable Loss of IZKF1 and IRF4 in KI-JK ALCL Tumors
- FIG. 12 is a graph of the tumor volume in mice administered Compound 1 or pomalidomide over the 21 -day period. As shown in Figure 12, the tumor volume decreased in mice administered Compound 1.
- a single dose of Vehicle, Pomalidomide (3000 ⁇ g/kg), or Compound 1 (30 or 100 ⁇ g/kg) was given to mice bearing KI-JK tumors. All compounds were formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Mice were sacrificed and tumors harvested at 6 and 24 hours post single dose. Tumors were mechanically homogenized, and protein extracted using RIPA buffer (Sigma Aldrich). Protein concentration was quantified using a PierceTM BCA Protein Assay Kit, samples were reduced, and equal protein amounts were then loaded onto a western blot gel for analysis.
- IKZF1 Invitrogen, PA5-23728
- IRF- 4 CST, 15106
- IKZF1 expression is shown in Figure 13 A
- IRF-4 expression is shown in Figure 13B.
- Data is expressed as percentage of IKZF1 or IRF-4 in comparison to the vehicle control and normalized to GAPDH levels to control for protein loading. Error bars represent ⁇ SEM values.
- the percentage of IKZF1 and IRF-4 was smaller in mice administered Compound 1 compared to mice administered pomalidomide at both the 6-hour and 24-hour timepoint.
- Example 18 Compound 1 induces Deep and Durable Loss of IZKF1 and IRF4 in DL-40
- a single dose of Vehicle, Pomalidomide (3000 ⁇ g/kg), or Compound 1 (30 or 100 ⁇ g/kg) was given to mice bearing DL-40 tumors. All compounds were formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- PEG400 30% v/v
- HPMC 1% w/v
- citrate buffer pH 5
- Mice dosed with Pomalidomide were sacrificed at 1, 4, and 24 hours post dose, with two mice sampled per timepoint.
- Mice in the Compound 1 groups were sampled at 1, 4, 24, and 48 hours post dose with four tumors collected per timepoint. Tumors were then mechanically homogenized, and protein extracted using RIP A buffer (Sigma Aldrich).
- Protein concentration was quantified using a PierceTM BCA Protein Assay Kit, samples were reduced, and equal protein amounts were then loaded onto a western blot gel for analysis as shown in Figure 15B.
- Samples were analyzed for IKZF1 (Invitrogen, PA5-23728) expression as shown in Figure 15 A. Data is expressed as percentage of IKZF1 in comparison to the vehicle control and normalized to GAPDH levels to control for protein loading. Error bars represent ⁇ SEM values.
- Example 19 Compound 1 Efficacy in Mice with DL-40 Tumors
- Table 8 Statistical Significance of Compound 1 Compared to Vehicle All agents were administered to mice bearing DL-40 tumors on day 0 and dosed PO daily for 21 days. Compound 1 was dosed at 3, 10, 30, 100, or 300 ⁇ g/kg and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Pomalidomide was dosed at 3000 ⁇ g/kg and used the same formulation as Compound 1. Body weight and MTV was measured on a 2x weekly schedule, and the study end point was a MTV of 2007 mm 3 in the vehicle control group on Day 21. Statistical analysis was performed using two-way analysis of variance (ANOVA). Data are expressed as MTV ⁇ SEM.
- Figure 16 is a graph of the tumor volume of mice administered with Compound 1 or pomalidomide over the course of 21 days, and shown, Compound 1 at 30, 100, and 300 ⁇ g/kg was able to reduce tumor volume.
- Figure 17 is a graph of the body weight changes of the mice over the 21 -day study period.
- Example 20 Compound 1 Promotes Robust Loss of IRF4 and Rise in Caspase 3 (MoA) and IRF-1 (BmX) in ALCL Model
- Compound 1 (100 ⁇ g/kg) and the vehicle control were administered to mice bearing KI- JK tumors on day 0 and dosed PO daily for 21 days.
- Compound 1 was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5), which was also used as the vehicle control.
- Body weight and MTV was measured on a 2x weekly schedule and the study end point was a MTV of 1885 mm 3 in the vehicle control group on Day 24. Data are expressed as MTV ⁇ SEM.
- Figure 18 is a graph of the tumor volume of the course of the study, and as shown, Compound 1 reduced tumor volume.
- a second xenograft study was conducted in female NOD SCID mice bearing KI-JK ALCL tumors.
- MTV mean tumor volume
- Compound 1 (100 ⁇ g/kg) or the vehicle control were dosed PO to mice bearing KI-JK tumors.
- Compound 1 was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- PEG400 30% v/v
- HPMC 1% w/v
- citrate buffer pH 5
- mice were sacrificed, and tumors harvested 24 hours post a single dose.
- Mice in the Compound 1 group were sampled at 4- and 24-hours post dose a single dose, with two tumors collected per time point. Additional mice were dosed daily for 5 or 7 days with tumor collections 24 hours post last dose, with 2 mice sampled per time point. Tumors were then mechanically homogenized, and protein extracted using RIPA buffer (Sigma Aldrich).
- Example 21 The combination of Compound 1 and Ibrutinib
- Treatment began on Day 0 with established subcutaneous TMD8 tumors with a mean tumor volume (MTV) of 107-108 mm 3 . All agents were administered to mice bearing TMD8 tumors on day 0 and dosed PO daily until individual tumor volumes reached or exceeded 1500 mm 3 , at which point dosing stopped and the individual mouse was removed from the study.
- Compound 1 was dosed at 50 ⁇ g/kg and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Ibrutinib was dosed at 12.5 mg/kg and formulated in 0.5% MC+0.4% cremophor EL+0.1% sodium lauryl sulfate.
- FIG. 1 is a graph of the tumor volume of mice administered with vehicle, Compound 1, Ibrutinib, or the combination of Compound 1 and Ibrutinib, and as shown, the combination was the most effective in reducing tumor volume.
- Figure 21 is a graph describing the percent survival of mice over the course of the study. The highest percentage of surviving mice was observed with the combination. Table 9 describes the statistical significance of the agent compared to vehicle and Table 10 describes the statistical significance of the combination compared to Ibrutinib and Compound 1.
- Example 22 The combination of Compound 1 and Dexamethasone
- mice bearing RPMI-8226 tumors All agents were administered to mice bearing RPMI-8226 tumors on day 0 and dosed until an individual moue tumor volume reached or exceeded 1000 mm 3 , at which point the mouse was removed from the study and dosing stopped.
- Compound 1 was dosed PO daily at 10 ⁇ g/kg and formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Dexamethasone was dosed IV once a week at 5000 ⁇ g/kg and formulated in saline.
- Compound 1 was also dosed in combination with Dexamethasone at their respective dose levels and schedules. Body weight and MTV were measured on a 2x weekly schedule.
- Figure 22 is a graph of the tumor volume of mice administered with vehicle, Compound 1, Dexamethasone, or the combination of Compound 1 and Dexamethasone, and as shown, the combination was most effective in reducing tumor volume. The highest percentage of surviving mice was observed with the combination ( Figure 23).
- Table 11 describes the statistical significance of the agent compared to vehicle and Table 12 describes the statistical significance of the combination compared to Ibrutinib and Compound 1. This data is also presented in Figure 41 and Figure 42.
- One fasted male cynomolgus monkey was administered Compound 1 formulated in 1% carboxymethylcellulose sodium + 20% PEG400 in citrate buffer at 30 ⁇ g/kg by oral gavage.
- blood was collected from a peripheral vessel from a restrained, non sedated monkey. 50 uL of whole blood was added to a flow tube with 1ml PBS, centrifuged for 5 minutes at 400 ⁇ g and supernatant discarded. Blood was lysed in ImL of lysis buffer for 10-15 minutes at room temperature, centrifuged for 5 minutes at 400 ⁇ and supernatant discarded. PBS (1 mL) was added to each tube, centrifuged for 5 minutes at 400 ⁇ g and supernatant discarded.
- PBS (1 mL) was added together with 1 ul of Zombie NIR dye to the white blood cells and incubated for 20 minutes at room temperature. The cells were centrifuged for 5 minutes at 400 ⁇ g and supernatant discarded. Fixation buffer (1 mL) was added and incubated for 20 minutes at room temperature. Cells were washed with permeabilization buffer (1 mL) and centrifuged for 5 minutes at 400 ⁇ g and supernatant discarded. Permeabilization buffer (1 mL) was added, incubated for 20min at room temperature, cells were centrifuged for 5 minutes at 400 ⁇ g and supernatant removed. Fc block (ImL) was added, incubated for 15 minutes at room temperature.
- FIG. 24 is a graph of the percent mean fluorescence intensity of IKZF1 and IZKF3 at 4h and 24hr post dose compared to the pre-dose sample. At both the 4-hour and 24-hour timepoint, the levels of IKZF1 and IKZF3 were smaller than the concentration at the pre-dose.
- Compound 1 was administered to a rat at a concentration of 30 mg/kg PO and monkeys at a concentration of either 60 ⁇ g/kg or 100 ⁇ g/kg PO.
- plasma samples were collected and the Cmax, half-life, and AUC 0-inf were determined for both Compound 1 and a metabolite of Compound 1, Compound 14.
- the percent of Compound 14 was also determined (Table 13).
- Figure 25A is a graph measuring the concentration of Compound 1 or Compound 14 over the course of 24 hours in monkeys administered 100 ⁇ g/kg or 60 ⁇ g/kg of Compound 1.
- Figure 25B is a graph measuring the concentration of Compound 1 or Compound 14 over the course of 24 hours in a rat administered 30 mg/kg of Compound 1.
- the compounds were dosed at 100 ⁇ g/kg and formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Body weight and MTV were measured on a 2x weekly schedule and the study end point was after 5 days of dosing.
- Figures 26A - Figure 26K and Figure 26M are graphs measuring the tumor volumes of the mice over the course of the study. Data are expressed as MTV ⁇ SEM.
- a second xenograft study was conducted in female NOD SCID mice bearing DL-40 ALCL tumors.
- the animals were divided randomly into groups of 2, stratified to result in about equal average tumor sizes in each treatment group.
- Treatment began on Day 0 with established subcutaneous DL-40 tumors with a mean tumor volume (MTV) of 242-244 mm 3 .
- MTV mean tumor volume
- Compound 12 and the vehicle control were administered to mice bearing DL-40 tumors on day 0 and dosed PO for 5 days.
- Compound 12 was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5).
- Body weight and MTV were measured on a 2x weekly schedule and the study end point was after 7 days of dosing.
- Figure 26L is a graph measuring the tumor volumes of the mice over the course of the 5-day study. Data are expressed as MTV ⁇ SEM.
- the cell permeability and binding affinity of Compound 1 and pomalidomide to cellular cereblon was determined by competitive displacement of a NanoBRETTM tracer reversibly bound to a cereblon-NanoLuc® fusion protein in 293T cells.
- 293T cells were modified by lentiviral transfection to express a fusion of cereblon and NanoLuc® luciferase.
- the modified cereblon- NanoLuc 293 T cell line was co-treated with varying concentrations of test compound and a probe conjugated with NanoBRET fluorescent tracer at its predetermined KD concentration (300 nM) and incubated for 2 hours at 37°C to reach equilibrium.
- test compound was determined by displacement of NanoBRET tracer signal following the addition of NanoBRET reagents (Promega).
- 10 mM DMSO test compound stock solution was serially diluted (half log) in DMSO to generate 11 -point dose series in an acoustic ready 384-well low dead volume microplate (Labcyte).
- NanoBRET TE Assay reagents 20 uL NanoBRET TE Assay reagents were added to each well and NanoBRET signal was acquired on an EnVision Multilabel Reader (PerkinElmer). Donor emission from cereblon-NanoLuc was detected at 450 nm with a NanoLuc 460/50 filter and Acceptor fluorescence of NanoBRET-pomalidomide tracer (618 nm) was detected with a 600 nm long pass NanoBRET filter. Ratio of Acceptor signal / Donor signal was calculated for each well. Column 24 (cells without NanoBRET-pomalidomide tracer addition) was used as positive control (P).
- Protein concentrations were measured using the BCA Protein Assay Kit (Thermo, 23228). Protein standard curve, prepared with BSA, and samples protein concentrations were read using the Envision Multilabel Reader (PerkinElmer). Lysate concentrations were normalized with lysis buffer and Laemmli 6X, SDS-Sample Buffer, Reducing (Boston BioProducts, Inc. Part #BP-111R- 50ml). Normalized samples and Chameleon® Duo Pre-stained Protein Ladder (LLCOR, 928- 60000) were loaded onto 4-15% CriterionTM Tris-HCl Protein Gel (Bio-Rad, #3450028). Gels ran at 120 V for 1.5 hours.
- TBS Intercept® Blocking Buffer
- Primary antibodies were diluted in Intercept® T20 (TBS) Protein- Free Antibody Diluent (LLCOR, catalog #927-85001) and incubated while rocking at 4°C overnight.
- Membranes were washed 3 times for 5 minutes in TBS-T while rocking. Secondary antibodies were diluted in Intercept® T20 (TBS) Protein-Free Antibody Diluent (LI-COR, catalog # 927-85001) and incubated on membranes for 1 hour while rocking at room temperature. Membranes were washed as previously described and imaged on the Odyssey CLx. Data are expressed as percentage of Aiolos or Ikaros in comparison to the vehicle control and normalized to ⁇ -actin control for sample loading. The resulting western blot is shown in Figure 30.
- Apoptosis induction in NCIH929 multiple myeloma cells was determined by measuring Caspase 3/7 activity following 72 hour treatment with Compound 1 using Caspase 3/7 Assay System (Promega, G8091). Briefly, test compound was added to white 384-well TC-treated plates at a top concentration of 100 nM for Compound 1 and 10 ⁇ M for pomalidomide with 10 points, half log titration in duplicates. 30 pL NCIH929 cells were seeded into the 384-well plates in RPMI medium containing 10% FBS and 0.05 mM 2-mercaptoethanol at a cell density of 1000 cells per well. Cells treated in the absence of the test compound were the negative control.
- test compound was added to 384-well plates at a top concentration of 100 nM for Compound 1 and 10 ⁇ M for pomalidomide with 10 points, half log titration in duplicates.
- 50 uL cells suspended in growth media at cell densities indicated for each cell line in Table 14 were dispensed using a Multidrop Combi Reagent Dispenser (Thermo Fisher) to 384-well black TC-treated microplates containing duplicate concentration range of test compounds and DMSO controls.
- Cells treated in the absence of the test compound were the negative control and cells treated in the absence of CellTiter-Glo® 2.0 were the positive control. Cells were incubated at 37 °C with 5% CO 2 for 96 hr. CellTiter-Glo reagent was then added to the cells and luminescence was acquired on EnVisionTM Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). % Viability was determined by normalizing the signal with positive and DMSO treated negative controls on the same microtiter plate. Compound 1 inhibited growth for all eight multiple myeloma cell lines with maximal inhibition greater than 50% and IC50s less than 1 nM and was 1000-fold more potent that pomalidomide. The resulting data is shown in Figure 32.
- Table 14 Multiple myeloma cell lines: source vendor, description of cancer cell type, growth medium conditions and experimental seeding density.
- Example 31 Compound 1 Efficacy in Multiple Myeloma
- Compound 1 efficacy in a multiple myeloma cell line was evaluated at four different concentrations: 3 ⁇ g/kg, 10 ⁇ g/kg, 30 ⁇ g/kg, and 100 ⁇ g/kg.
- Compound 1 was administered QD (every day) orally (PO).
- the efficacy of Compound 1 was compared to pomalidomide (administered at 3000 ⁇ g/kg).
- the results in the NCI-H929 are shown in FIG 7.
- Table 15 describes the statistical significance of the experiment for each dose. Treatment with Compound 1 at all 10, 30 and 100 ⁇ g/kg resulted in a reduced tumor volume more than pomalidomide administered at 3000 ⁇ g/kg.
- Table 15 Statistical Significance of Compound 1 Compared to Vehicle
- NCI-H929 cells For the NCI-H929 cells, the xenograft study was conducted in female NOD SCID mice bearing NCI-H929 multiple myeloma tumors.
- Compound 1 was dosed at 3, 10, 30, or 100 ⁇ g/kg and was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5). Pomalidomide was dosed at 3000 ⁇ g/kg and used the same formulation as Compound 1. Body weight and MTV were measured on a 2x weekly schedule. After the initial 21 days of dosing, all Compound 1 groups were monitored for tumor growth. The 10 ⁇ g/kg group was removed from study on 39.
- a xenograft study was conducted in female CB 17 SCID mice bearing RPMI-8226 multiple myeloma tumors.
- Compound 1 (100 ⁇ g/kg) and the vehicle control were administered to mice bearing RPMI- 8226 tumors on day 0 and dosed PO daily for 5 days.
- Compound 1 was formulated in PEG400 (30% v/v) + 70%v/v HPMC (1% w/v) in citrate buffer (pH 5), which was also used as the vehicle control.
- Body weight and MTV was measured on a 2x weekly schedule.
- 3 mice were sacrificed, and tumors harvested 24 hours post a single dose.
- Mice in the Compound 1 group were sampled at 4- and 24-hours post dose a single dose, with 3 tumors collected per time point. Additional mice were dosed daily for 3 or 5 days with tumor collections 24 hours post last dose, with 3 mice sampled per time point.
- Tumors were then mechanically homogenized, and protein extracted using RIPA buffer (Sigma Aldrich). Protein concentration was quantified using a PierceTM BCA Protein Assay Kit, samples were reduced, and equal protein amounts were then loaded onto a western blot gel for analysis. Tumors were analyzed for IKZF1 (Invitrogen, PA5-23728), IKZF3 (CST, 15103), or IRF-4 (CST, 15106) expression. The intensity of individual bands was measured for data analysis using Image Studio NIR software. Protein expression was quantitated in relation to the reference protein, GAPDH, to control for total protein concentration. The data was then normalized to the amount of target in the Compound 1 treated samples in comparison to the vehicle control samples. Data is represented as percent of target present in the vehicle control and normalized for total protein. Error bars represent ⁇ SEM values. This study was used to produce the data in Figure 36 and Figure 37.
- Cells were cultured in lOuM lenalidomide for two months. A portion of the cells were then passaged into luM pomalidomide or continued to be cultured in lenalidomide in parallel for an additional two months. Cells were lysed in RIPA with protease inhibitors and 30ug of protein were loaded into each well of a 4-12%T TGX gel and run for 90 minutes at 120 volts. Protein was transferred to a nitrocellulose membrane and blotted for indicated protein (cereblon: Sigma catalog
- Example 34 Compound 1 Retains Activity in IMiD- Resistant H929 MM Cells
Abstract
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AU2021322285A AU2021322285A1 (en) | 2020-08-07 | 2021-08-06 | Advantageous therapies for disorders mediated by Ikaros or Aiolos |
CN202180066994.5A CN116194438A (en) | 2020-08-07 | 2021-08-06 | Advantageous treatment of Ikaros or Aiolos mediated disorders |
JP2023507879A JP2023538520A (en) | 2020-08-07 | 2021-08-06 | Advantageous treatments for disorders mediated by IKAROS or AIOLOS |
MX2023001545A MX2023001545A (en) | 2020-08-07 | 2021-08-06 | Advantageous therapies for disorders mediated by ikaros or aiolos. |
BR112023002225A BR112023002225A2 (en) | 2020-08-07 | 2021-08-06 | METHOD FOR TREATMENT OF A DISORDER MEDIATED BY IKAROS AND/OR AIOLOS |
CA3173658A CA3173658A1 (en) | 2020-08-07 | 2021-08-06 | Advantageous therapies for disorders mediated by ikaros or aiolos |
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KR1020237007995A KR20230049678A (en) | 2020-08-07 | 2021-08-06 | Beneficial therapy for disorders mediated by Ikaros or Aiolos |
EP21853504.5A EP4192450A1 (en) | 2020-08-07 | 2021-08-06 | Advantageous therapies for disorders mediated by ikaros or aiolos |
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WO2023025112A1 (en) * | 2021-08-27 | 2023-03-02 | 杭州格博生物医药有限公司 | Isoindolinone compound and use thereof |
WO2023154417A1 (en) * | 2022-02-09 | 2023-08-17 | C4 Therapeutics, Inc. | Morphic forms of cft7455 and methods of manufacture thereof |
US11807620B2 (en) | 2020-02-21 | 2023-11-07 | Plexium, Inc. | Quinazolinone compounds and related compounds |
WO2024073507A1 (en) | 2022-09-28 | 2024-04-04 | Theseus Pharmaceuticals, Inc. | Macrocyclic compounds and uses thereof |
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US20180008574A1 (en) * | 2015-01-28 | 2018-01-11 | Guangzhou Institutes of Biomediciene and Health, Chinese Academy of Sciences | 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof |
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WO2012175481A1 (en) * | 2011-06-20 | 2012-12-27 | Institut Curie | Compositions and methods for treating leukemia |
US20180008574A1 (en) * | 2015-01-28 | 2018-01-11 | Guangzhou Institutes of Biomediciene and Health, Chinese Academy of Sciences | 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof |
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