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WO2024173833A1 - Combinaison d'un inhibiteur de cdk et d'un inhibiteur de flt3 destinée au traitement du cancer - Google Patents

Combinaison d'un inhibiteur de cdk et d'un inhibiteur de flt3 destinée au traitement du cancer Download PDF

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Publication number
WO2024173833A1
WO2024173833A1 PCT/US2024/016215 US2024016215W WO2024173833A1 WO 2024173833 A1 WO2024173833 A1 WO 2024173833A1 US 2024016215 W US2024016215 W US 2024016215W WO 2024173833 A1 WO2024173833 A1 WO 2024173833A1
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Prior art keywords
anticancer agent
cancer
inhibitor
cdk inhibitor
effective amount
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Inventor
Daniel P. Gold
Sandra E. Wiley
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Lite Strategy Inc
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Mei Pharma Inc
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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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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

Definitions

  • phase III trials The failure rate in phase III trials is almost 50%, and the cost of new drug development from discovery through phase III trials is between $0.8 billion and $1.7 billion and can take between eight and ten years.
  • many patients fail to respond even to standard drugs that have been shown to be efficacious. For reasons that are not currently well understood or easily evaluated, individual patients may not respond to standard drug therapy.
  • administration of drug combinations may be more efficacious for treating cancer than drugs administered individually. These drug combinations may act synergistically to enhance the anti-cancer activity of the drugs.
  • drugs that are not particularly efficacious may find new and unexpected uses when combined with additional drug therapies.
  • the disclosure provides method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK inhibitor of Formula Ib: Ib, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the cancer is relapsed and/or refractory.
  • the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma
  • AML acute myeloid leuk
  • the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia, or chronic lymphocytic leukemia. In some embodiments, the blood cancer is relapsed and/or refractory acute myeloid leukemia. In some embodiments, the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • pancreatic cancer intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), u
  • the method further comprising administering to the subject a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the CDK inhibitor and the first anticancer agent are administered concurrently, the CDK inhibitor and the second anticancer agent are administered concurrently, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently.
  • the CDK inhibitor and the first anticancer agent are administered sequentially, the CDK inhibitor and the second anticancer agent are administered sequentially, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 5 hours of each other, the CDK inhibitor and the second anticancer agent are administered sequentially within about 5 hours of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 5 hours of each other.
  • the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition
  • the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the first anticancer agent are administered daily, every other day, or every third day
  • the CDK inhibitor and the second anticancer agent are administered daily, every other day, or every third day
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered daily, every other day, or every third day.
  • the present disclosure provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the method further comprises administering to the subject a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the cancer is relapsed and/or refractory. In one embodiment, the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia. In one embodiment, the blood cancer is relapsed and/or refractory acute myeloid leukemia. In one embodiment, the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • pancreatic cancer intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial
  • the CDK inhibitor and the first anticancer agent are administered concurrently, the CDK inhibitor and the second anticancer agent are administered concurrently, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently.
  • the CDK inhibitor and the first anticancer agent are administered sequentially, the CDK inhibitor and the second anticancer agent are administered sequentially, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially within about 5 hours of each other, the CDK inhibitor and the second anticancer agent are administered sequentially within about 5 hours of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially within about 5 hours of each other.
  • the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition
  • the CDK inhibitor and the second anticancer agent are co- formulated in a pharmaceutical composition
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the first anticancer agent are administered daily, every other day, or every third day
  • the CDK inhibitor and the second anticancer agent are administered daily, every other day, or every third day
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered daily, every other day, or every third day.
  • the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor, and a pharmaceutically acceptable excipient.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX- 925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the pharmaceutical composition further comprises a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A- 1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the present disclosure provides a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: b, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor for use in a method of treating a cancer.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX- 925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor is further used in the method of treating the cancer.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A- 1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the cancer is relapsed and/or refractory. In one embodiment, the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B- cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia. In one embodiment, the blood cancer is relapsed and/or refractory acute myeloid leukemia. In one embodiment, the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • pancreatic cancer intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial
  • the CDK inhibitor and the first anticancer agent are administered concurrently to a subject, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to a subject, the CDK inhibitor and the second anticancer agent are administered sequentially to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to a subject.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 5 hours of each other, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 5 hours of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 5 hours of each other.
  • the CDK inhibitor and first anticancer agent are co-formulated in a pharmaceutical composition
  • the CDK inhibitor and the second anticancer agent are co- formulated in a pharmaceutical composition
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day
  • the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day.
  • Figs.2A and 2B illustrate dose response curves representations of cytostatic vs cytotoxic compound activity.
  • Figs.3A and 3B illustrate decreased c-MYC expression in solid tumors: 10 gene biomarkers evaluated in Phase 1 daily dosing study; c-MYC expression decreased in 17/25 patients (68%).
  • Figs.4A-4C illustrate CR in a patient with pulmonary metastases; Fig.4A: baseline CT scan; Fig.4B: 2 months after starting the trial, radiological CR based on official radiological report; Fig.4C: 14 months after starting the trail, patient remained on trial for 12 months only, and CR remained durable for 14 months.
  • Figs.5A-5D illustrate that Voruciclib shows preferential tumor accumulation in a preclinical model.
  • DETAILED DESCRIPTION [0015] While preferred embodiments are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the disclosure, and various alternatives to the described embodiments of the disclosure may be employed.
  • the disclosure provides combination therapies for the treatment of cancer.
  • the disclosure provides combination therapies of CDK inhibitors with FLT3 inhibitors for treating cancer.
  • Such combination provides synergistic effects in the treatment of cancers and particularly treatment of blood cancers, e.g., leukemia and lymphoma.
  • the general terms used hereinbefore and hereinafter preferably have the following meanings within the context of this disclosure, unless otherwise indicated.
  • the term can mean within an order of magnitude, within 5-fold, and within 2-fold, of a value.
  • the term “at least one” is refers to one or more.
  • the term “at least one anticancer agent” means that the combination comprises a single anticancer agent or more anticancer agents.
  • the term “effective amount” or “therapeutically effective amount,” as used herein, generally refers to an amount of a compound described herein that is sufficient to affect an intended, predetermined or prescribed application, including but not limited to, disease or condition treatment.
  • the therapeutically effective amount can vary depending upon the application (e.g., in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition and the manner of administration.
  • the term also may apply to a dose that induces a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein.
  • the specific dose may vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • the term “free base dosage” refers to an amount of drug in its free base form, which can be replaced by an amount of a salt of the drug by using a salt conversion factor.
  • the term “pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. “Pharmaceutically acceptable” also means that the compositions or dosage forms are within the scope of sound medical judgment, suitable for use for an animal or human without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “combination” or “pharmaceutical combination” refers to the combined administration of the anticancer agents.
  • Combinations of the disclosure include a CDK inhibitor, e.g., a compound of Formula I, Ia, or Ib, and at least an additional therapeutic agent, e.g., an anti-cancer agent, which anti-cancer agents may be administered to a subject in need thereof, e.g., concurrently or sequentially.
  • the terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or once daily.
  • the terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day, or twice daily.
  • a “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • solid form may refer to a crystalline solid form or phase, including a crystalline free base and a crystalline salt.
  • co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.
  • an effective amount refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment.
  • a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells (e.g., CDK inhibition).
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions, including fumarate, maleate, phosphate, L-tartrate, esylate, besylate, hydrobromide, hydrochloride, citrate, gentisate, oxalate, sulfate counter ions, and the like.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients can also be incorporated into the described compositions.
  • the term “in vivo” refers to an event that takes place in a subject’s body.
  • the term “in vitro” refers to an event that takes places outside of a subject’s body.
  • In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
  • extragranular refers to substances that are outside of a granule, e.g., a substance added to granules (multiparticle compacts formed by a granulation process) and physically mixed with granules, but not contained within the granules.
  • Intragranular refers to substances that are within a granule (a multiparticle compact formed by a granulation process).
  • Granules may be formed by processes such as wet granulation (i.e., prepared using moisture or steam, thermal, melt, freeze, foam, and other processes) or dry granulation.
  • the term “acidulant” refers to a substance that increases acidity.
  • the terms “reflection” or “reflection mode,” when used in conjunction with powder X- ray diffraction refers to the reflection (also known as Bragg-Brentano) sampling mode.
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13C- or 14C-enriched carbons are within the scope of this disclosure.
  • ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the synergistic effect can be greater than about 10 %, 20 %, 30 %, 50 %, 75 %, 100 %, 110 %, 120 %, 150 %, 200 %, 250 %, 350 %, or 500% or more than the effect on a subject with one of the components alone, or the additive effects of each of the components when administered individually.
  • the effect can be any of the measurable effects described herein.
  • synergy between the agents when combined may allow for the use of smaller doses of one or both agents, may provide greater efficacy at the same doses, and may prevent or delay the build-up of multi-drug resistance.
  • the combination index (CI) method of Chou and Talalay may be used to determine the synergy, additive or antagonism effect of the agents used in combination.
  • CI value When the CI value is less than 1, there is synergy between the compounds used in the combination; when the CI value is equal to 1, there is an additive effect between the compounds used in the combination and when CI value is more than 1, there is an antagonistic effect.
  • the synergistic effect may be attained by co-formulating the agents of the pharmaceutical combination.
  • CDKs Cyclin-dependent kinases
  • CDKs are a family of enzymes which become activated in specific phases of the cell cycle.
  • CDKs consist of a catalytic subunit (the actual cyclin- dependent kinase or CDK) and a regulatory subunit (cyclin).
  • CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, etc. There are at least nine CDKs (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, etc.) and at least 15 different types of cyclins (cyclin A, B1, B2, D1, D2, D3, E, H etc.).
  • CDK inhibitor refers to an agent that is capable of inhibiting one or more cyclin dependent kinases (CDK). Aberrant expression and overexpression of these kinases are evidenced in many disease conditions such as cancer.
  • CDK inhibitor of the pharmaceutical combination described herein may be a compound of Formula I, Ia, or Ib or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure may inhibit one or more of CDK1/cyclin B, CDK2/cyclin E, CDK4/cyclin D, CDK4/cyclin D1 and CDK9/cyclin T1 with specificity.
  • a compound of the disclosure inhibits CDK9/cyclin T1 or CDK9 with specificity.
  • combination therapies for the treatment of cancer e.g., leukemia, lymphoma and breast cancer.
  • the methods and compositions described herein may include a cyclin-dependent kinase (CDK) inhibitor, such as a compound of Formula I, Ia, or Ib or a pharmaceutically acceptable salt thereof.
  • CDK cyclin-dependent kinase
  • a CDK inhibitor of the disclosure is represented by a compound disclosed in U.S. Pat Nos.7,271,193; 7,915,301; 8,304,449; 7,884,127; 8,563,596, the entire contents of each of which are incorporated herein by reference.
  • a CDK inhibitor of the disclosure is represented by Formula I: or a pharmaceutically acceptable salt thereof , wherein: R1 is optionally substituted phenyl; R 2 and R 3 are each independently selected from hydroxy and OR 8 , wherein R 8 is optionally substituted C1-C10-alkyl; R 4 is optionally substituted C 1 -C 4 -alkyl; and R9 is hydrogen or optionally substituted C1-C4-alkyl.
  • the compound or salt of Formula I is represented by Formula I [0046]
  • R1 is optionally substituted with one or more substituents independently selected from hydroxy, cyano, halo, amino, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, and nitro.
  • R 1 is substituted with one or more substituents independently selected from hydroxy, cyano, halo, C1-C4-alkyl, and C1-C4-haloalkyl.
  • R1 is substituted with one or more substituents independently selected from halo and C 1 -C 4 - haloalkyl. In certain embodiments, R1 is 2-chloro-4-trifluoromethylphenyl.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, and containing no unsaturation. In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C 1 -C 5 alkyl).
  • an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C 1 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C 2 -C 5 alkyl).
  • an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • alkyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • alkoxy refers to a radical bonded through an oxygen atom of the formula – O-alkyl, where alkyl is an alkyl chain as defined above.
  • amino refers to the group –NR’R”, wherein R’ and R” are independently selected from hydrogen; and alkyl, hydroxyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, any one of which may be optionally substituted with one or more substituents such as hydroxy, cyano, halo, amino, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, and nitro.
  • Cx-y when used in conjunction with a chemical moiety, such as alkyl is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • haloalkyl refers to an alkyl group that is substituted by one or more halo radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the haloalkyl is further optionally substituted as described herein.
  • hydroxyalkyl refers to an alkyl group that is substituted by one or more hydroxy radicals, for example, hydroxymethyl, hydroxyethyl, dihydroxymethyl, and the like.
  • R 8 at each occurrence is selected from optionally substituted C1-C6-alkyl, such as optionally substituted C1-C4-alkyl.
  • R2 and R3 are each independently hydroxy.
  • R4 is optionally substituted C1-C2-alkyl.
  • R4 is hydroxyalkyl, e.g., 2-hydroxymethyl.
  • R9 is optionally substituted C1-C2-alkyl.
  • R9 is methyl.
  • R 9 is hydrogen.
  • a compound of Formula I is a compound or pharmaceutically acceptable salt selected from: (+)-trans-2-(2- Chloro-4-trifluoromethylphenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7- dimethoxy-chromen-4-one; (+)-trans-2-(2-Chloro-4-trifluoromethylphenyl)-5,7-dihydroxy-8- (2-hydroxymethyl-1-methylpyrrolidin-3-yl)-chromen-4-one; and (+)-trans-2-(2-Chloro-4- trifluoromethylphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)- chromen-4-one hydrochloride.
  • the compound of Formula I or Ia is represented by Formula Ib: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I, Ia, or Ib is in the form of an acid addition salt, such as the hydrochloride salt.
  • the CDK inhibitor of the disclosure is a polymorph of Formula Ib (i.e. voruciclib) disclosed in International Application No. WO 2020/210760 (PCT/US2020/027847), which is incorporated by reference herein.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, as well as represents a stable compound, which does not readily undergo transformation such as rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxy, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sul
  • Procedures for the manufacture of the compounds of Formula I, Ia, and Ib or the pharmaceutically acceptable salts thereof may be found in PCT Patent Publication No. WO2004004632 (corresponding to U.S. Patent 7,271,193) and PCT Patent Publication No. WO2007148158.
  • the present disclosure provides pharmaceutically-acceptable salts of any compound described herein, e.g., a compound of Formula I, Ia, Ib.
  • Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts.
  • the acid that is added to a compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to a compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically-acceptable salt is an ammonium salt.
  • Acid addition salts can arise from the addition of an acid to a compound described herein. In some cases, the acid is organic. In some cases, the acid is inorganic.
  • Non-limiting examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-aminosalicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, glycolic acid, malic acid, malonic acid, cinnamic acid, mandelic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, phenylacetic acid, N-cyclohexylsulf
  • Metal salts can arise from the addition of an inorganic base to a compound of the disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound described herein.
  • Non-limiting examples of suitable organic amines include triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzyl amine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, pipyrazine, ethylenediamine, N,N’-dibenzylethylene diamine, procaine, chloroprocaine, choline, dicyclohexyl amine, and N- methylglucamine.
  • Non-limiting examples of suitable ammonium salts include is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzyl amine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, a pipyrazine salt, an ethylene diamine salt, an N,N’-dibenzylethylene diamine salt, a procaine salt, a chloroprocaine salt, a choline salt, a dicyclohexyl amine salt, and a N-methylglucamine salt.
  • Non-limiting examples of suitable acid addition salts include a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, a malonate salt, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, a bicarbonate salt, a nicotinate salt, an isonicotinate salt, a lactate salt, a salicylate salt, a 4-aminosalicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure).
  • Stereoisomers may also be obtained by stereoselective synthesis.
  • the compounds described herein e.g., the compounds and salts of Formulas I, Ia, Ib, include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the compounds described herein include compounds that exhibit their natural isotopic abundance, and compounds where one or more of the atoms are artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically-enriched compounds may be prepared.
  • Compounds described herein, e.g., the compounds and salts of Formulas I, Ia, Ib, wherein the compound has carbon-carbon double bonds or carbon-nitrogen double bonds may exist, where applicable, in Z- or E- form (or cis- or trans- form).
  • some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
  • a compound described herein may be a prodrug, e.g., wherein a carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents, i.e., parent compound, of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as enzymatic activity in specific target cells in the host animal.
  • esters or carbonates are preferred prodrugs of the present disclosure.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug.
  • the prodrug may have improved cell permeability over the parent compound.
  • the prodrug may also have improved solubility in pharmaceutical formulations over the parent drug.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility.
  • a cyclin-dependent kinase (CDK) inhibitor e.g., a compound or salt of Formula I, Ia or Ib
  • an additional therapeutic agent e.g., an anti-cancer agent.
  • the additional therapeutic agent is a first anticancer agent comprising a FLT3 inhibitor.
  • the first anticancer agent is a FLT3 inhibitor.
  • the one or more additional therapeutic agents further comprise a second anticancer agent comprising a BCL-2 inhibitor.
  • the second anticancer agent is a BCL-2 inhibitor.
  • the CDK inhibitor (e.g., a compound of Formula I, Ia, Ib, or a pharmaceutically acceptable salt thereof), may be used in combination with a FLT3 inhibitor.
  • FLT3 is a receptor tyrosine kinase expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system.
  • the ligand for FLT3 is expressed by marrow stromal cells and other cells and synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells.
  • FLT3 is gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis.
  • This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor.
  • the activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia.
  • Mutations of FLT3 have been detected in about 30% of patients with acute myelogenous leukemia and a small number of patients with acute lymphocytic leukemia or myelodysplastic syndrome. Patients with FLT3 mutations tend to have a poor prognosis. The mutations most often involve small tandem duplications of amino acids within the juxtamembrane domain of the receptor and result in constitutive tyrosine kinase activity. Expression of a mutant FLT3 receptor in murine marrow cells results in a lethal myeloproliferative syndrome and preliminary studies suggest that mutant FLT3 cooperates with other leukemia oncogenes to confer a more aggressive phenotype.
  • FLT3 Upon activation, FLT3 undergoes a conformational change involving flipping of three residues, Asp-Phe-Gly, or DFG; active and inactive conformations are called DFG-in and DFG-out, respectively. All FLT3 inhibitors interact with the ATP-binding site of the intracellular TKD and competitively inhibit ATP binding, thereby preventing receptor autophosphorylation and activation of downstream signaling. However type I FLT3 inhibitors bind to the ATP-binding site when the receptor is active, while type II FLT3 inhibitors interact with a hydrophobic region immediately adjacent to the ATP-binding site that is only accessible when the receptor is in the inactive conformation, and they prevent receptor activation.
  • D835 is the most common site for TKD mutations and D835 mutations favor the active conformation. Consequently type I inhibitors inhibit FLT3 signaling in AML cells with either ITD or TKD mutations, while type II inhibitors inhibit FLT3 with ITD, but not with TKD mutations, though some D835 mutations preserve sensitivity [12]. Importantly, development of D835 mutations in cells with ITD is a mechanism of acquired, or secondary, resistance to type II FLT3 inhibitors. Type I inhibitors include sunitinib, lestaurtinib, midostaurin, crenolanib and gilteritinib, while type II inhibitors include sorafenib, quizartinib and ponatinib.
  • FLT3 inhibitor refers to a compound which interacts with the ATP-binding site of the intracellular TKD and competitively inhibits ATP binding.
  • the FLT3 inhibitor is used in combination with a compound or salt of Formula I, Ia, or Ib. Any FLT3 inhibitor may be used and may exhibit a synergistic effect when used in combination with a compound or salt of Formula I, Ia, or Ib.
  • a compound or salt of Formula I, Ia, or Ib is used in combination with FLT3 inhibitor described elsewhere herein.
  • the compound or salt of Formula I, Ia, or Ib, and the FLT3 inhibitor is used further in combination with a BCL-2 inhibitor.
  • a cyclin-dependent kinase (CDK) inhibitor e.g., a compound or salt of Formula I, Ia, or Ib, and a FLT3 inhibitor
  • CDK cyclin-dependent kinase
  • Inhibitors of BCL-2 anti- apoptotic family of proteins alter at least a cell survival pathway. Apoptosis activation may occur via an extrinsic pathway triggered by the activation of cell surface death receptors or an intrinsic pathway triggered by developmental cues and diverse intracellular stresses.
  • BCL-2 anti-apoptotic proteins having BH1-BH4 domains
  • BCL-2 anti-apoptotic proteins having BH1-BH4 domains
  • BCL-xL BCL-w
  • A1, MCL-1 BCL-1
  • BCL-B pro-apoptotic proteins having BH1, BH2, and BH3 domains
  • BAX, BAK, and BOK pro-apoptotic BH3-only proteins
  • BIK, BAD, BID, BIM, BMF, HRK, NOXA, and PUMA pro-apoptotic BH3-only proteins
  • BCL-2 anti-apoptotic proteins block activation of pro-apoptotic multi-domain proteins BAX and BAK (see, e.g., Adams et al., Oncogene 26:1324-37 (2007)).
  • BCL-2 inhibitor refers to an agent that is capable of inhibiting one or more proteins in the BCL-2 family of anti-apoptotic proteins, e.g., BCL-2, BCL-xL, and BCL-w.
  • a BCL-2 inhibitor of the disclosure inhibits one protein of the BCL-2 family selectively, e.g., a BCL-2 inhibitor may selectively inhibit BCL-2 and not BCL-xl or BCL-w.
  • the BCL-2 inhibitor described herein may inhibit one or more of BCL-2, BCL-xL, and BCL-w.
  • the inhibitor of BCL-2 anti-apoptotic family of proteins inhibits BCL-2.
  • the inhibitor of BCL-2 anti-apoptotic family of proteins inhibits BCL-2 and does not inhibit other members of the BCL-2 family of proteins, e.g., does not inhibit BCL-xL or BCL-w.
  • the BCL-2 inhibitor is a BH3-mimetic.
  • the BCL-2 inhibitor of the disclosure inhibits BCL-xL function.
  • the inhibitor may also interact with and/or inhibit one or more functions of BCL-2, e.g., BCL-xL/BCL-2 inhibitors.
  • a BCL-2 inhibitor of the disclosure inhibits each of BCL-xL and BCL-w.
  • a BCL-2 inhibitor of the disclosure inhibits BCL-xL, BCL-2, and BCL-w.
  • a BCL-2 inhibitor interferes with the interaction between the BCL-2 anti-apoptotic protein family member and one or more ligands or receptors to which the BCL-2 anti-apoptotic protein family member would bind in the absence of the inhibitor.
  • an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least one BCL-2 protein specifically, binds only to one or more of BCL-xL, BCL-2, BCL-w and not to other Bcl-2 anti-apoptotic Bcl-2 family members, such as Mcl-1 and BCL2A1.
  • Binding affinity of a BCL-2 inhibitor for BCL-2 family proteins may be measured.
  • binding affinity of a BCL-xL inhibitor may be determined using a competition fluorescence polarization assay in which a fluorescent BAK BH3 domain peptide is incubated with BCL-xL protein (or other BCL-2 family protein) in the presence or absence of increasing concentrations of the BCL-XL inhibitor as previously described (see, e.g., U.S. Patent Publication 20140005190; Park et al., Cancer Res.73:5485-96 (2013); Wang et al., Proc. Natl. Acad. Sci USA 97:7124-9 (2000); Zhang et al., Anal. Biochem.307:70-5 (2002); Bruncko et al., J. Med.
  • Percent inhibition may be determined by the equation: 1-[(mP value of well – negative control)/range)] x 100%.
  • BCL-2 inhibitors include ABT-263 (4-[4-[[2-(4-chlorophenyl)-5,5- dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1- phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide or IUPAC, (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfon
  • the BCL-2 inhibitor is a quinazoline sulfonamide compound (see, e.g., Sleebs et al., 2011, J. Med. Chem.54:1914).
  • the BCL- inhibitor is a small molecule compound as described in Zhou et al., J. Med.
  • the BCL-2 inhibitor is a BCL-2/BCL-xL inhibitor such as BM-1074 (see, e.g., Aguilar et al., 2013, J. Med. Chem.56:3048); BM-957 (see, e.g., Chen et al., 2012, J. Med. Chem.55:8502); BM-1197 (see, e.g., Bai et al., PLoS One 2014 Jun 5;9(6):e99404. Doi: 10.1371/journal.pone.009904); U.S. Patent Appl. No.2014/0199234; N- acylsufonamide compounds (see, e.g., Int’l Patent Appl. Pub.
  • BM-1074 see, e.g., Aguilar et al., 2013, J. Med. Chem.56:3048
  • BM-957 see, e.g., Chen et al., 2012, J. Med. Chem.55
  • the BCL-2 inhibitor is a small molecule macrocyclic compound (see, e.g., Int’l Patent Appl. Pub. No. WO 2006/127364, U.S. Pat. No.7777076).
  • the BCL-2 inhibitor is an isoxazolidine compound (see, e.g., Int’l Patent Appl. Pub. No. WO 2008/060569, U.S. Pat. No.
  • the BCL-2 inhibitor is S44563 (see, e.g., Loriot et. al., Cell Death and Disease, 2014, 5, e1423).
  • the BCL-2 inhibitor is (R)-3-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4- (dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)-2,3,4,4a,5,6- hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxamide.
  • the BCL-2 inhibitor is a small molecule heterocyclic compounds (see, e.g.,U.S. Pat. No.9018381).
  • a BCL-2 inhibitor is used in combination with a compound or salt of Formula I, Ia, or Ib. Any BCL-2 inhibitor may be used and may exhibit a synergistic effect when used in combination with a compound or salt of Formula I, Ia, or Ib.
  • a BCL-2 family inhibitor may inhibit one or more members of the BCL-2 family, including Bcl-2, Bcl-xL, Bcl- w, BAK1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L2, BCL2L10, BCL2L13, BCL2L14, BOK and MCL1.
  • a compound or salt of Formula I, Ia, or Ib is used in combination with any of the following: navitoclax, venetoclax, A-1155463, A-1331852, ABT- 737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, ARRY 520 trifluoroacetate, BH3I-1, antimycin A, chelerythrine, gossypol (NSC19048), apogossypol (NSC736630), 4-(3-methoxy- phenylsulfonyl)-7-nitro-benzofurazan-3-oxide (MNB), TM12-06, ABT-263, BDA-366, o
  • voruciclib is used in combination with navitoclax or a pharmaceutically acceptable salt thereof. In certain embodiments, voruciclib is used in combination with venetoclax or a pharmaceutically acceptable salt thereof.
  • Crystalline Forms [0088] In an embodiment, the disclosure provides a crystalline solid form of Formula Ib (i.e., voruciclib). In an embodiment, the disclosure provides a crystalline solid form of voruciclib free base. In an embodiment, the disclosure provides a crystalline solid form of a voruciclib salt. The disclosure provides polymorphs, for example crystal forms, of voruciclib. In some embodiments, the polymorphs include free base voruciclib.
  • the polymorphs include voruciclib salts including a counterion corresponding to an acid selected from 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, ortho-phosphoric acid, sulfuric acid, p-toluenesulfonic acid, and the like.
  • Any crystalline form described herein can be characterized by X-ray diffraction.
  • X-ray diffraction refers to X-ray powder diffraction.
  • X-ray diffraction may be measured using transmission mode or reflection mode.
  • the X-ray diffraction pattern of any embodiments herein is measured in transmission mode.
  • the X-ray diffraction pattern of any embodiments herein is measured in reflection mode. It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation, or instrument used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may vary depending on measurement conditions and sample preparation.
  • Different crystalline form may provide surprising advantages compared to non- crystalline forms, including improved thermodynamic stability, faster dissolution rate, improved performance in the stomach and gastric environment (including the avoidance of, or reduced, precipitation from solution upon a change to higher pH), improved exposure in mammals, and superior processability for formulation of drug into finished products suitable for patients.
  • the disclosure provides a crystal form of voruciclib malonate, and/or a polymorph crystal form of voruciclib malonate (Mao1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from:
  • each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ 0.3°.
  • the disclosure provides a crystal form of voruciclib malonate, and/or a polymorph crystal form of voruciclib malonate (Mao1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from: In some embodiments, each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ 0.3°. [0093] In one embodiment, the disclosure provides a crystal form of voruciclib oxalate, and/or a polymorph crystal form of voruciclib oxalate (Oxa1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from:
  • each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ [0094]
  • the disclosure provides a crystal form of voruciclib oxalate, and/or a polymorph crystal form of voruciclib oxalate (Oxa1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from:
  • each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ 0.3°.
  • the disclosure provides a crystal form of voruciclib phosphate, and/or a polymorph crystal form of voruciclib phosphate (Pho1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from:
  • each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ 0.3°.
  • the disclosure provides a crystal form of voruciclib phosphate, and/or a polymorph crystal form of voruciclib phosphate (Pho1), characterized by an X-ray powder diffraction pattern including one or more peaks selected from:
  • each peak independently may include a variation of ⁇ 0.1°, ⁇ 0.2°, or ⁇ 0.3°.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 7.30° ⁇ 0.2°, 13.58° ⁇ 0.2°, 14.06° ⁇ 0.2°, 15.18° ⁇ 0.2°, 15.66° ⁇ 0.2°, 17.50° ⁇ 0.2°, 18.94° ⁇ 0.2°, 19.54° ⁇ 0.2°, 22.22° ⁇ 0.2°, 23.38° ⁇ 0.2°, 24.10° ⁇ 0.2°, 24.98° ⁇ 0.2°, 25.94° ⁇ 0.2°, 27.26° ⁇ 0.2°, 28.50° ⁇ 0.2°, and 32.82° ⁇ 0.2° 2 ⁇ .
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib malonate. In some embodiments, the crystal form includes hydrated voruciclib malonate. In some embodiments, the crystal form includes anhydrous voruciclib malonate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 6.36° ⁇ 0.2°, 7.31° ⁇ 0.2°, 9.34° ⁇ 0.2°, 10.05° ⁇ 0.2°, 13.59° ⁇ 0.2°, 13.88° ⁇ 0.2°, 14.08° ⁇ 0.2°, 15.21° ⁇ 0.2°, 15.67° ⁇ 0.2°, 17.53° ⁇ 0.2°, 18.70° ⁇ 0.2°, 18.98° ⁇ 0.2°, 19.38° ⁇ 0.2°, 19.67° ⁇ 0.2°, 20.16° ⁇ 0.2°, 20.39° ⁇ 0.2°, 21.01° ⁇ 0.2°, 22.27° ⁇ 0.2°, 23.35° ⁇ 0.2°, 24.15° ⁇ 0.2°, 24.67° ⁇ 0.2°, 25.00° ⁇ 0.2°, 25.18° ⁇ 0.2°,
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib malonate. In some embodiments, the crystal form includes hydrated voruciclib malonate. In some embodiments, the crystal form includes anhydrous voruciclib malonate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 5.06° ⁇ 0.2°, 6.42° ⁇ 0.2°, 9.34° ⁇ 0.2°, 10.14° ⁇ 0.2°, 12.30° ⁇ 0.2°, 13.66° ⁇ 0.2°, 14.14° ⁇ 0.2°, 15.82° ⁇ 0.2°, 17.02° ⁇ 0.2°, 19.74° ⁇ 0.2°, 20.38° ⁇ 0.2°, 21.82° ⁇ 0.2°, 22.66° ⁇ 0.2°, 24.62° ⁇ 0.2°, 25.78° ⁇ 0.2°, 26.58° ⁇ 0.2°, 28.66° ⁇ 0.2°, and 29.98° ⁇ 0.2° 2 ⁇ .
  • the X- ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib dibenzoyl-tartrate. In some embodiments, the crystal form includes hydrated voruciclib dibenzoyl-tartrate. In some embodiments, the crystal form includes anhydrous voruciclib dibenzoyl-tartrate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 4.94° ⁇ 0.2°, 6.78° ⁇ 0.2°, 9.34° ⁇ 0.2°, 10.94° ⁇ 0.2°, 12.70° ⁇ 0.2°, 13.38° ⁇ 0.2°, 14.90° ⁇ 0.2°, 15.66° ⁇ 0.2°, 17.54° ⁇ 0.2°, 18.82° ⁇ 0.2°, 22.02° ⁇ 0.2°, 23.98° ⁇ 0.2°, 24.78° ⁇ 0.2°, 25.30° ⁇ 0.2°, 26.66° ⁇ 0.2°, and 29.98° ⁇ 0.2° 2 ⁇ .
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib phosphate. In some embodiments, the crystal form includes hydrated voruciclib phosphate. In some embodiments, the crystal form includes anhydrous voruciclib phosphate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 4.93° ⁇ 0.2°, 6.79° ⁇ 0.2°, 9.35° ⁇ 0.2°, 10.58° ⁇ 0.2°, 10.91° ⁇ 0.2°, 12.64° ⁇ 0.2°, 13.35° ⁇ 0.2°, 13.58° ⁇ 0.2°, 14.81° ⁇ 0.2°, 15.60° ⁇ 0.2°, 17.18° ⁇ 0.2°, 17.52° ⁇ 0.2°, 18.32° ⁇ 0.2°, 18.78° ⁇ 0.2°, 19.34° ⁇ 0.2°, 19.64° ⁇ 0.2°, 19.78° ⁇ 0.2°, 22.02° ⁇ 0.2°, 23.20° ⁇ 0.2°, 23.67° ⁇ 0.2°, 24.00° ⁇ 0.2°, 24.71° ⁇ 0.2°, 25.21° ⁇ 0.2°, 25
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib phosphate. In some embodiments, the crystal form includes hydrated voruciclib phosphate. In some embodiments, the crystal form includes anhydrous voruciclib phosphate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 6.86° ⁇ 0.2°, 12.66° ⁇ 0.2°, 13.58° ⁇ 0.2°, 14.74° ⁇ 0.2°, 15.98° ⁇ 0.2°, 19.38° ⁇ 0.2°, 23.94° ⁇ 0.2°, 24.78° ⁇ 0.2°, and 25.94° ⁇ 0.2° 2 ⁇ .
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib oxalate. In some embodiments, the crystal form includes hydrated voruciclib oxalate. In some embodiments, the crystal form includes anhydrous voruciclib oxalate. [0103] In one embodiment, the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 6.86° ⁇ 0.2°, 9.70° ⁇ 0.2°, 10.84° ⁇ 0.2°, 12.50° ⁇ 0.2°, 12.66° ⁇ 0.2°, 12.81° ⁇ 0.2°, 13.41° ⁇ 0.2°, 13.71° ⁇ 0.2°, 14.54° ⁇ 0.2°, 15.35° ⁇ 0.2°, 15.83° ⁇ 0.2°, 18.70° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.43° ⁇ 0.2°, 19.62° ⁇ 0.2°, 21.75° ⁇ 0.2°, 22.75° ⁇
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib oxalate. In some embodiments, the crystal form includes hydrated voruciclib oxalate. In some embodiments, the crystal form includes anhydrous voruciclib oxalate.
  • the disclosure provides a crystal form of voruciclib characterized by an X-ray powder diffraction pattern including one or more peaks selected from 9.02° ⁇ 0.2°, 10.50° ⁇ 0.2°, 11.06° ⁇ 0.2°, 12.30° ⁇ 0.2°, 12.82° ⁇ 0.2°, 13.90° ⁇ 0.2°, 14.82° ⁇ 0.2°, 15.30° ⁇ 0.2°, 15.94° ⁇ 0.2°, 17.26° ⁇ 0.2°, 19.34° ⁇ 0.2°, 20.62° ⁇ 0.2°, 22.18° ⁇ 0.2°, 22.86° ⁇ 0.2°, 24.58° ⁇ 0.2°, 25.42° ⁇ 0.2°, 25.86° ⁇ 0.2°, 27.38° ⁇ 0.2°, and 28.66° ⁇ 0.2° 2 ⁇ .
  • the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or the like, selected from the above group of peaks.
  • the crystal form includes voruciclib napadisylate. In some embodiments, the crystal form includes hydrated voruciclib napadisylate. In some embodiments, the crystal form includes anhydrous voruciclib napadisylate.
  • Pharmaceutical compositions [0105] In certain embodiments, the disclosure provides a pharmaceutical composition, e.g., for oral or parenteral administration, comprising a compound or salt of Formula I, Ia, or Ib.
  • the pharmaceutical composition comprises a compound or salt of Formula I, Ia, or Ib in an amount of at least about 1 mg to about 1000 mg, from about 100 mg to about 400 mg, from about 100 mg to about 200 mg, from about 200 mg to about 400 mg, or from about 250 mg to about 350 mg.
  • a pharmaceutical composition of the disclosure may comprise about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 500 mg of a compound of Formula I, Ia, or Ib.
  • the amount of the compound may reflect the free base weight and not the weight of the salt form.
  • the pharmaceutical composition of the compound or salt of Formula I, Ia, or Ib does not include the first anticancer agent. In certain embodiments, the pharmaceutical composition includes the first anticancer agent. In certain embodiments, the pharmaceutical composition of the compound or salt of Formula I, Ia, or Ib does not include the second anticancer agent. In certain embodiments, the pharmaceutical composition includes the second anticancer agent. In certain embodiments, the pharmaceutical composition of the compound or salt of Formula I, Ia, or Ib does not include the first anticancer agent or the second anticancer agent. In certain embodiments, the pharmaceutical composition includes the first anticancer agent and the second anticancer agent.
  • a therapeutically effective amount of a compound of the disclosure can be expressed as mg of the compound per kg of subject body mass.
  • a dose of a therapeutically effective amount may be at least about 0.1 mg/kg to about 20 mg/kg, for example, about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, or about 20 mg/kg.
  • the therapeutically effective amount of the compound may reflect the free base weight and not the weight of the salt form.
  • the disclosure provides a pharmaceutical composition, e.g., for oral or parenteral administration, comprising an additional therapeutic agent, e.g., anticancer agent, in an amount of at least about 1 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, or from about 300 mg to about 8000 mg.
  • a pharmaceutical composition of the disclosure may comprise about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, about 800 mg, about 820 mg, about 840 mg, about 860 mg, about 880 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, or about 1000 mg of an additional therapeutic agent, e.g., anticancer agent.
  • an additional therapeutic agent e.g.,
  • the amounts of the solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day.
  • a solid form of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, is administered in a single dose.
  • such administration will be by injection, for example by intravenous injection, in order to introduce the active pharmaceutical ingredients quickly.
  • other routes may be used as appropriate.
  • a single dose of a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, may also be used for treatment of an acute condition.
  • a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day.
  • a solid form of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, is administered about once per day to about 6 times per day.
  • the administration of the solid forms of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein continues for less than about 7 days.
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • Administration of the active pharmaceutical ingredients of the disclosure may continue as long as necessary.
  • a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • the solid forms of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • an effective dosage of voruciclib is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about
  • an effective dosage of a solid form of voruciclib is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.
  • an effective dosage of a solid form of voruciclib is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.
  • an effective daily dosage of a solid form of voruciclib free base, or its calculated salt and/or salt polymorph equivalent amount is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.
  • an effective daily dosage of a solid form of voruciclib free base, or its calculated salt and/or salt polymorph equivalent amount is a tolerable dosage determined by one skilled in the art, for example less than about 25 mg, less than about 50 mg, less than about 75 mg, less than about 100 mg, less than about 125 mg, less than about 150 mg, less than about 175 mg, less than about 200 mg, less than about 225 mg, less than about 250 mg, less than about 275 mg, less than about 300 mg, less than about 325 mg, less than about 350 mg, less than about 375 mg, less than about 400 mg, less than about 425 mg, less than about 450 mg, less than about 475 mg, or less than about 500 mg.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a dosage refers to a daily dosage.
  • exact amounts and/or dosages can be corrected for drug substance assay (free base on the anhydrous, solvent free basis). Salt conversion factor can also be derived by one skilled in the art.
  • the malonate salt conversion factor is 0.8187, such that 61.07 mg of voruciclib malonate equals 50 mg of voruciclib free base and 121.14 mg of voruciclib malonate equals 100 mg of voruciclib free base.
  • an effective dosage of voruciclib is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg
  • an effective dosage of a solid form of voruciclib is about 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a solid form of voruciclib including any voruciclib free base polymorph described herein, any voruciclib salt polymorph described herein, is administered at a dosage of 10 to 400 mg once daily (QD), including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg once daily (QD).
  • QD 10 to 400 mg once daily
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a solid form of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, is administered at a dosage of 10 to 400 mg BID, including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg BID.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a solid form of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, is administered at a dosage of 10 to 400 mg TID, including a dosage of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg TID.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • An effective amount of a solid form of voruciclib may be administered in either single or multiple doses by any of the accepted modes of administration of active pharmaceutical ingredients having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • the compositions and methods described herein can be used to overcome the effects of acid reducing agents. Acid-reducing agents can greatly limit the exposure of weakly acidic drugs in mammals. Smelick, et al., Mol.
  • Acid reducing agents include proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H2 receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium, as well as mixtures of antacids with agents targeting mechanisms of gastric secretion.
  • proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole
  • H2 receptor antagonists such as cimetidine, ranitidine, and famotidine
  • antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant selected from the group consisting of fumaric acid, tartaric acid, ascorbic acid, alginic acid, sodium alginate, potassium alginate, and Carbopol 971P (carboxypolymethylene).
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-araboascorbic acid), alginic acid, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), Carbomer 941 (polyacrylic acid), and Carbopol 971P (carboxypolymethylene).
  • an acidulant selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-araboascorbic acid), alg
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the acidulant is extragranular.
  • the acidulant is intragranular.
  • Alginic acid is a polysaccharide copolymer, ⁇ -D-mannuronic acid (M) and ⁇ -L- guluronic acid (G) linked by 1-4 glycosidic bonds.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant that is an alginic acid or salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of between 0.1 and 0.5, between 0.2 and 0.6, between 0.3 and 0.7, between 0.4 and 0.8, between 0.5 and 0.9, between 0.6 and 1.0, between 0.7 and 1.1, between 0.8 and 1.2, between 0.9 and 1.3, between 1.0 and 1.4, between 1.1 and 1.5, between 1.2 and 1.6, between 1.3 and 1.7, between 1.4 and 1.8, between 1.5 and 1.9, between 1.6 and 2.0, between 1.7 and 2.1, between 1.8 and 2.2, between 1.9 and 2.3, between 2.0 and 2.4, and between 2.1 and 2.5.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant that is an alginic acid or salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of less than 0.5, less than 1.0, less than 1.5, less than 2.0, and less than 2.5.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant that is an alginic acid or salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of greater than 0.5, greater than 1.0, greater than 1.5, greater than 2.0, and greater than 2.5.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant that is an alginic acid or salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, and 2.5.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl- tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • M/G ratio as well as the fraction of M and G groups, the fractions of MM and GG “diads,” the fractions of “triads” (e.g., MGG), and the fractions of larger sequences of M and G groups, may be determined by methods known to those of ordinary skill in the art, including nuclear magnetic resonance (NMR) spectroscopy (with or without digestion) and mass spectrometry.
  • NMR nuclear magnetic resonance
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, and between 30% and 35%.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, and between 30% and 35%, wherein the acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D- araboascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene).
  • a concentration selected from the group consisting of between 1% and 5%, between
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%, wherein the acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D- araboascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene).
  • a concentration selected from the group consisting of less than 1%, less than 5%, less than
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, and greater than 35%.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, and greater than 35%, wherein the acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-araboascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene).
  • a concentration selected from the group consisting of greater than 1%, greater than 5%, greater than
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, and about 40%.
  • concentration % mass
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant in a concentration (% mass) selected from the group consisting of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, and about 40%, wherein the acidulant is selected from the group consisting of fumaric acid, succinic acid, D- tartaric acid, L-tartaric acid, race
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-araboascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene), and combinations thereof.
  • the extragranular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is fumaric acid at a concentration of between about 15% to about 33% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is alginic acid or a salt thereof (such as sodium alginate or potassium alginate) at a concentration of between about 5% to about 33% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is L-tartaric acid at a concentration of between about 25% to about 33% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is ascorbic acid at a concentration of between about 20% to about 50% by weight and Carbopol 971P (carboxypolymethylene) at a concentration of between about 2.5% to about 10% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is fumaric acid at a concentration of between about 5% to about 15% by weight and alginic acid or a salt thereof at a concentration of about 15% to about 33% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is L-tartaric acid at a concentration of between about 5% to 15% by weight and alginic acid at a concentration of between about 15% to about 33% by weight.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant, wherein the acidulant is selected from the group consisting of fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid, and sulfuric acid.
  • a pharmaceutical composition comprises voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and an acidulant, wherein the acidulant is selected from the group consisting of fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid, and sulfuric acid, and wherein the acidulant is a salt counterion included in any crystalline form described herein.
  • a pharmaceutical composition in addition to an acidulant, includes an excipient to prolong the exposure of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, to the acidic microenvironment.
  • this excipient is a polymer of natural, synthetic or semisynthetic origins.
  • the polymer may contain acidic, anionic, or non-ionic monomers, oligomers or polymers or a mixture of acidic, anionic and non-ionic monomers or copolymers.
  • the excipient is selected from the group consisting of hydroxypropylmethylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, tocopherol polyethyleneoxide succinate (D- ⁇ -tocopherol polyethylene glycol succinate, TPGS, or vitamin E TPGS), methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylacrylate, ethylacrylate, co-polymers of methyl and ethyl acrylate, hydroxypropylmethylcellulose acetate succinate, gelatin, maize starch, pea starch, modified maize starch, potato starch, modified potato starch, sodium starch glycolate, croscarmellose, crospovidone, copovidone, polyethylene glycol, polypropylene glycol, polyethylene and polypropylene glycol copolymers, polyvinylalcohol, polyvinylalcohol and polyethylene oxide copolymers.
  • tocopherol polyethyleneoxide succinate D- ⁇ -tocophe
  • Copolymers of the foregoing polymers may also be used.
  • Copolymers may be block, branched or terminal copolymers.
  • the polymer exhibits swelling, binding, or gelling properties that inhibit the disintegration, dissolution, and erosion of the pharmaceutical composition in order to prolong dissolution or to increase total dissolution.
  • the inclusion of the polymer increases dissolution rate and extent of dissolution over the use of an acidulant alone.
  • the swelling, binding or gelling properties are pH-dependent in one embodiment, wherein the polymer swells, binds, or gels at one pH or range of pH in a different manner than at another pH. In one embodiment this may decrease dissolution at a lower pH than at a higher pH or vice versa.
  • voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, in acidic, neutral or basic pH.
  • the dissolution profile of a formulation containing one or more swelling, gelling, or binding excipients may exhibit a zero, first, or second differential rate order at one or more pH value or a mixture of different rate orders at different pH values.
  • a pharmaceutical composition will provide a constant level of drug into the gastrointestinal tract of a mammal by dissolution.
  • voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein
  • this leads to a sustained plasma level of drug over a period, delays the t max , and reduces the c max of an equivalent dose of an immediate release formulation voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein. In another embodiment this leads to similar exposure in a mammal regardless of stomach pH.
  • Methods of Treatment [0130]
  • the pharmaceutical compositions described herein can be used in a method for treating diseases. In preferred embodiments, they are for use in treating hyperproliferative disorders. They may also be used in treating other disorders as described herein and in the following paragraphs.
  • the present disclosure provides a method of treating a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a CDK inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the present disclosure provides a method of treating a cancer in a subject with a FLT3 mutation.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP- 7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • method further comprises administering to the subject a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A- 1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, ARRY 520 trifluoroacetate, pelcitoclax, BH3I-1, antimycin A, chelerythrine, gossypol (NSC19048), apogossypol (NSC736630), 4-(3-methoxy-phenylsulfonyl)-7-
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the cancer is relapsed and/or refractory.
  • the cancer is a blood cancer.
  • the blood cancer is leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), and lymphoblastic leukemia.
  • the blood cancer is a non-Hodgkin lymphoma, such as B-cell or T-cell lymphoma.
  • B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • SLL small lymphocytic lymphoma
  • mantle cell lymphoma marginal zone B-cell lymphomas
  • extranodal marginal zone B-cell lymphomas nodal marginal zone B-cell lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • T- cell lymphomas include precursor T-lymphoblastic lymphoma, peripheral T-cell lymphomas, cutaneous T-cell lymphomas, adult T-cell lymphoma with subtypes: smoldering chronic, acute, and lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, nasal type, enteropathy-associated intestinal T-cell lymphoma (EATL) with subtypes I and II, and anaplastic large cell lymphoma (ALCL).
  • the blood cancer is multiple myeloma. Combinations of the present disclosure may be used to treat a blood cancer described herein.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • the terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the disclosure provides methods of preventing, or reducing, a relapse of a cancer in a subject in need thereof.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound or combination that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • the method includes administering a combination therapy described herein to treat minimal residual disease, and/or as maintenance therapy, e.g., as a prolonged or extended therapy after cessation of another cancer treatment.
  • the combination therapy may be administered after cessation of another cancer therapy, such as chemotherapy, radiation therapy and/or surgery.
  • a proteasome inhibitor may be combined or used in combination with a CDK inhibitor of the disclosure, e.g., a compound or salt of any one of Formulas I, Ia, or Ib.
  • a CDK inhibitor of the disclosure e.g., a compound or salt of any one of Formulas I, Ia, or Ib.
  • Ub ubiquitin
  • UPS proteasome pathway
  • the E1 first activates Ub and transfers it to E2. From the E2 enzyme, the Ub is transferred directly to the target protein or indirectly through an E3 Ub ligase.
  • the polyubiquitylated protein is recognized and degraded by 26S proteasome, a large complex with multiple proteolytic activities.
  • a combination therapy described herein can reduce the likelihood of metastasis in a subject in need thereof.
  • the metastasis is a solid tumor.
  • the metastasis is a liquid tumor.
  • Cancers that are liquid tumors can be those that occur, for example, in blood, bone marrow, and lymph nodes, and can include, for example, leukemia, myeloid leukemia, lymphocytic leukemia, lymphoma, Hodgkin’s lymphoma, melanoma, and multiple myeloma.
  • Leukemias include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and hairy cell leukemia.
  • Cancers that are solid tumors include, for example, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi’s sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head and neck cancers, throat cancer, squamous carcinomas that form on the moist mucosal linings of the nose, mouth, throat, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and kidney cancer.
  • the condition treated by the methods described herein is metastasis of melanoma cells, prostate cancer cells, testicular cancer cells, breast cancer cells, brain cancer cells, pancreatic cancer cells, colon cancer cells, thyroid cancer cells, stomach cancer cells, lung cancer cells, ovarian cancer cells, Kaposi’s sarcoma cells, skin cancer cells, renal cancer cells, head or neck cancer cells, throat cancer cells, squamous carcinoma cells, bladder cancer cells, osteosarcoma cells, cervical cancer cells, endometrial cancer cells, esophageal cancer cells, liver cancer cells, or kidney cancer cells.
  • the methods described herein can also be used for inhibiting progression of metastatic cancer tumors.
  • Non-limiting examples of cancers include adrenocortical carcinoma, childhood adrenocortical carcinoma, AIDS-related cancers, anal cancer, appendix cancer, basal cell carcinoma, childhood basal cell carcinoma, bladder cancer, childhood bladder cancer, bone cancer, brain tumor, childhood astrocytomas, childhood brain stem glioma, childhood central nervous system atypical teratoid/rhabdoid tumor, childhood central nervous system embryonal tumors, childhood central nervous system germ cell tumors, childhood craniopharyngioma brain tumor, childhood ependymoma brain tumor, breast cancer, childhood bronchial tumors, carcinoid tumor, childhood carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma of unknown primary, childhood carcinoma of unknown primary, childhood cardiac tumors, cervical cancer, childhood cervical cancer, childhood chordoma , chronic myeloproliferative disorders, colon cancer, colorectal cancer, childhood colorectal cancer, extrahepatic bile duct cancer , ductal carcinoma in
  • the combination therapies described herein may be used together with other therapies such as radiation therapy.
  • Chemotherapy and radiotherapy treatment regimens can comprise a finite number of cycles of on-drug therapy followed by off-drug therapy, or comprise a finite timeframe in which the chemotherapy or radiotherapy is administered.
  • the protocols can be determined by clinical trials, drug labels, and clinical staff in conjunction with the subject to be treated.
  • the number of cycles of a chemotherapy or radiotherapy or the total length of time of a chemotherapy or radiotherapy regimen can vary depending on the subject’s response to the cancer therapy.
  • a pharmaceutical agent described herein can be administered after the treatment regimen of chemotherapy or radiotherapy has been completed.
  • the combinations described herein can be utilized to treat a subject in need thereof.
  • the subject to be treated by methods and compositions disclosed herein can be a human subject.
  • a subject to be treated by methods and compositions disclosed herein can be a non-human animal.
  • Non-limiting examples of non-human animals can include a non-human primate, a livestock animal, a domestic pet, and a laboratory animal.
  • the disclosure provides a method of treating a hyperproliferative disorder in a mammal that comprises administering to the mammal a therapeutically effective amount of a crystalline solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, or a pharmaceutical composition comprising a crystalline solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, as described herein.
  • the mammal is a human.
  • the hyperproliferative disorder is cancer.
  • the cancer is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström’s macroglobulinemia.
  • the cancer is selected from the group consisting of non-Hodgkin’s lymphomas (such as diffuse large B-cell lymphoma), acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, bone (e.g., metastatic bone), esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi’s sarcoma), viral-induced cancers such as cervical carcinoma (human papillomavirus), B-cell lymphoproliferative disease and nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi’s sarcoma and
  • the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hypertrophy (BPH)).
  • BPH benign prostatic hypertrophy
  • the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder.
  • the hyperproliferative disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet’s disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, instaenitis suppurativa, Sjögren’s syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’
  • the solid form of voruciclib including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the method of any of the foregoing embodiments further comprises the step of administering a FLT3 inhibitor to the mammal. Exemplary FLT3 inhibitors are described elsewhere herein.
  • the method of any of the foregoing embodiments further comprises the step of administering a FLT3 inhibitor and a BCL-2 inhibitor to the mammal.
  • a FLT3 inhibitor and a BCL-2 inhibitor Exemplary BCL-2 inhibitors are described elsewhere herein.
  • the method of any of the foregoing embodiments further includes the step of administering an acid reducing agent to the mammal.
  • the acid reducing agent is selected from the group consisting of proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H2 receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium.
  • proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole
  • H2 receptor antagonists such as cimetidine, ranitidine, and famotidine
  • antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium.
  • the disclosure provides pharmaceutical compositions of a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, for use in the treatment of cancers such as thymus cancer, brain cancer (e.g., glioma), lung cancer, squamous cell cancer, skin cancer (e.g., melanoma), eye cancer, retinoblastoma cancer, intraocular melanoma cancer, oral cavity cancer, oropharyngeal cancer, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, colon cancer, esophageal cancer, testicular cancer, gynecological cancer, ovarian cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancer (e.g., lymphoma and Kaposi’
  • cancers such as th
  • the disclosure provides pharmaceutical compositions of a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • the disclosure provides pharmaceutical compositions of a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, for use in the treatment of disorders such as myeloproliferative disorders (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABL1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis.
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • PMF primary myelofibrosis
  • BCR-ABL1-positive chronic neutrophilic leukemia
  • chronic neutrophilic leukemia chronic eosinophilic leukemia, or mast
  • compositions for use in treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and hemangioma.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the disclosure provides a method of treating a solid tumor cancer with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein.
  • the disclosure provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer, or a blood cancer.
  • the disclosure provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or a blood cancer using a combination of a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, and a second agent selected from the group consisting of bendamustine, venetoclax, vemurafenib, abraxane, enasidenib, pomalidomide, lenalidomide, azacitidine, decitabine, a hypomethylating agent, gemcitabine, albumin-bound paclitaxel, rituximab, obinutuzumab, ofatumumab
  • the disclosure provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or a blood cancer using a combination of a CDK inhibitor and bendamustine, venetoclax, vemurafenib, abraxane, enasidenib, pomalidomide, lenalidomide, azacitidine, decitabine, a hypomethylating agent, gemcitabine, albumin-bound paclitaxel, rituximab, obinutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, atezolizumab,
  • the proteasome inhibitor is selected from bortezomib, marizomib, ixazomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfil
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the disclosure provides a method of treating a solid tumor cancer with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein.
  • the disclosure provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer.
  • the disclosure provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein.
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the disclosure relates to a method of treating an inflammatory, immune, or autoimmune disorder in a mammal with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein.
  • the disclosure also relates to a method of treating a disease with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, wherein the disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet’s disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the disclosure relates to a method of treating a hyperproliferative disorder in a mammal with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, wherein the hyperproliferative disorder is a B cell hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin’s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt’s lymphoma, Waldenström’s macroglobulinemia (WM), Burkitt’s lymphoma, multiple myeloma, myelodysplastic syndrome
  • CLL chronic lymphoc
  • the disclosure relates to a method of treating a hyperproliferative disorder in a mammal with a composition including a solid form of voruciclib, including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein, wherein the hyperproliferative disorder is selected from the group consisting of chronic myelocytic leukemia, acute myeloid leukemia, DLBCL (including activated B-cell (ABC) and germinal center B-cell (GCB) subtypes), follicle center lymphoma, Hodgkin’s disease, multiple myeloma, indolent non-Hodgkin’s lymphoma, and mature B-cell ALL.
  • the hyperproliferative disorder is selected from the group consisting of chronic myelocytic leukemia, acute myeloid leukemia, DLBCL (including activated B-cell (ABC) and germinal center B-cell (GCB) subtypes), follicle center lymphoma,
  • the solid form of voruciclib in any of the foregoing embodiments is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib napadisylate, each as described herein.
  • the hyperproliferative disorder is a subtype of CLL. A number of subtypes of CLL have been characterized. CLL is often classified for immunoglobulin heavy-chain variable-region (IgV H ) mutational status in leukemic cells.
  • IgV H immunoglobulin heavy-chain variable-region
  • the disclosure relates to a method of treating a CLL in a human, wherein the CLL is selected from the group consisting of IgV H mutation negative CLL, ZAP-70 positive CLL, ZAP-70 methylated at CpG3 CLL, CD38 positive CLL, chronic lymphocytic leukemia characterized by a 17p13.1 (17p) deletion, and CLL characterized by a 11q22.3 (11q) deletion.
  • the hyperproliferative disorder is a CLL wherein the CLL has undergone a Richter’s transformation.
  • the hyperproliferative disorder is a CLL or SLL in a patient, wherein the patient is sensitive to lymphocytosis.
  • the disclosure relates to a method of treating CLL or SLL in a patient, wherein the patient exhibits lymphocytosis caused by a disorder selected from the group consisting of a viral infection, a bacterial infection, a protozoal infection, or a post-splenectomy state.
  • a disorder selected from the group consisting of a viral infection, a bacterial infection, a protozoal infection, or a post-splenectomy state.
  • the viral infection in any of the foregoing embodiments is selected from the group consisting of infectious mononucleosis, hepatitis, and cytomegalovirus.
  • the bacterial infection in any of the foregoing embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.
  • the hyperproliferative disorder is a blood cancer.
  • the blood cancer is leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).
  • leukemia such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).
  • the blood cancer is a non-Hodgkin lymphoma, such as B-cell or T-cell lymphoma.
  • B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B- cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • SLL small lymphocytic lymphoma
  • mantle cell lymphoma marginal zone B-cell lymphomas
  • extranodal marginal zone B-cell lymphomas nodal marginal zone B- cell lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • T-cell lymphomas include precursor T-lymphoblastic lymphoma, peripheral T-cell lymphomas, cutaneous T-cell lymphomas, adult T-cell lymphoma with subtypes: smoldering chronic, acute, and lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, nasal type, enteropathy-associated intestinal T-cell lymphoma (EATL) with subtypes I and II, and anaplastic large cell lymphoma (ALCL).
  • treatment of any of the foregoing disease/disorder embodiments further comprises the administration a first anticancer agent comprising a FLT3 inhibitor.
  • treatment of any of the foregoing disease/disorder embodiments further comprises the administration the first anticancer agent and a second anticancer agent comprising a BCL-2 inhibitor.
  • exemplary FLT3 inhibitors and BCL-2 inhibitors are described elsewhere herein.
  • the combination therapies described herein may be administered as separate agents or may be combined into a single pharmaceutical composition.
  • the CDK inhibitor and first anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • any of the forgoing methods comprise the concurrent administration of the CDK inhibitor and the first anticancer agent to the subject. In another embodiment, any of the forgoing methods comprise the sequential administration of the CDK inhibitor and the first anticancer agent to the subject. In one embodiment, any of the forgoing methods comprise the concurrent administration of the CDK inhibitor and the second anticancer agent to the subject. In another embodiment, any of the forgoing methods comprise the sequential administration of the CDK inhibitor and the second anticancer agent to the subject. In one embodiment, any of the forgoing methods comprise the concurrent administration of the CDK inhibitor, the first anticancer agent, and the second anticancer agent to the subject.
  • any of the forgoing methods comprise the sequential administration of the CDK inhibitor, the first anticancer agent, and the second anticancer agent to the subject.
  • the first anticancer agent comprises a FLT3 inhibitor.
  • the CDK inhibitor and the first anticancer agent are administered to sequentially to the subject within about 48 hours, about 40 hours, about 36 hours, about 30 hours, about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other.
  • the CDK inhibitor and the second anticancer agent are administered to sequentially to the subject within about 48 hours, about 40 hours, about 36 hours, about 30 hours, about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to sequentially to the subject within about 48 hours, about 40 hours, about 36 hours, about 30 hours, about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other. [0160] In one embodiment, the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 5 hours of each other. In one embodiment, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 5 hours of each other.
  • compositions disclosed herein may be in the form of a liquid formulation, a solid formulation or a combination thereof.
  • Non-limiting examples of formulations may include a tablet, a capsule, a pill, a gel, a paste, a liquid solution and a cream.
  • the therapeutic agent e.g., compound or salt of Formula I, Ia, or Ib, may be in a crystallized form.
  • each agent may be crystallized separately and then combined or they may be crystallized together.
  • compositions may comprise two or more therapeutic agents in one or more physical state.
  • a composition may be a tablet comprising one therapeutic agent in a solid formulation and another therapeutic agent or drug in a gel formulation.
  • the composition is a single pharmaceutical composition comprising a compound or salt of Formula I, Ia, or Ib in a first physical state and an additional therapeutic agent, e.g., anticancer agent such as a FLT3 inhibitor, in a second physical state.
  • the composition is a single pharmaceutical composition comprising a compound or salt of Formula I, Ia, or Ib in a first physical state and the first anticancer agent in a second physical state.
  • the compositions of the present disclosure may further comprise an excipient or an additive.
  • Excipients may include any and all solvents, coatings, chelating agents, flavorings, colorings, lubricants, disintegrants, preservatives, sweeteners, anti-foaming agents, buffering agents, polymers, antioxidants, binders, diluents, and vehicles (or carriers). Generally, the excipient is compatible with the therapeutic compositions of the present disclosure.
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicles before use.
  • Such liquid preparations can be prepared by conventional approaches with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); and artificial or natural colors and/or sweeteners.
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid
  • compositions and dosage forms of the present disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Compositions and dosage forms of the present disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous composition can be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions can be packaged using materials that prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic, unit dose containers, blister packs, and strip packs. [0165]
  • An ingredient described herein can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • suitable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters
  • Binders suitable for use in dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone,
  • suitable fillers for use in the compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the active ingredient therein can be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the composition can include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
  • a solubilizer can also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • Pharmaceutical compositions described herein may be suitable for oral administration to a subject in need thereof.
  • slow release formulations for oral administration may be prepared in order to achieve a controlled release of the active agent in contact with the body fluids in the gastrointestinal tract, and to provide a substantial constant and effective level of the active agent in the blood plasma.
  • the crystal form may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water-soluble polymer or a mixture of both, and optionally suitable surfactants.
  • the compositions can be formulated in a food composition.
  • the compositions can be a beverage or other liquids, solid food, semi-solid food, with or without a food carrier.
  • the compositions can include a black tea supplemented with any of the compositions described herein.
  • the composition can be a dairy product supplemented any of the compositions described herein.
  • the compositions can be formulated in a food composition.
  • the compositions can comprise a beverage, solid food, semi-solid food, or a food carrier.
  • the pharmaceutical formulations can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include, for example, aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared, for example, as oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, isopropyl palmitate, or medium chain triglycerides, or liposomes.
  • a formulation for parenteral administration is an aqueous suspension.
  • the compound described herein may be present in a composition within a range of concentrations, the range being defined by an upper and lower value selected from any of the preceding concentrations.
  • the compound or salt of the disclosure may be present in the formulation at a concentration of from about 1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.
  • Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [0176] Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • a composition described herein e.g., a pharmaceutical composition of a compound or salt of Formula I, Ia, or Ib, or an additional therapeutic agent, e.g., anticancer agent, or a co- formulation of a compound of Formula I, Ia, or Ib with an additional therapeutic agent, e.g., anticancer agent, can be administered once or more than once each day.
  • the composition may be administered serially (e.g., taken every day without a break for the duration of the treatment regimen).
  • the treatment regime can be less than a week, a week, two weeks, three weeks, a month, or greater than a month.
  • a composition of the disclosure is administered over a period of at least 12 weeks.
  • the composition is administered for a day, at least two consecutive days, at least three consecutive days, at least four consecutive days, at least five consecutive days, at least six consecutive days, at least seven consecutive days, at least eight consecutive days, at least nine consecutive days, at least ten consecutive days, or at least greater than ten consecutive days.
  • a therapeutically effective amount can be administered one time per week, two times per week, three times per week, four times per week, five times per week, six times per week, seven times per week, eight times per week, nine times per week, 10 times per week, 11 times per week, 12 times per week, 13 times per week, 14 times per week, 15 times per week, 16 times per week, 17 times per week, 18 times per week, 19 times per week, 20 times per week, 25 times per week, 30 times per week, 35 times per week, 40 times per week, or greater than 40 times per week.
  • a therapeutically effective amount can be administered one time per day, two times per day, three times per day, four times per day, five times per day, six times per day, seven times per day, eight times per day, nine times per day, 10 times per day, or greater than 10 times per day.
  • the composition is administered at least twice a day.
  • compositions of the disclosure are administered at least every hour, at least every two hours, at least every three hours, at least every four hours, at least every five hours, at least every six hours, at least every seven hours, at least every eight hours, at least every nine hours, at least every 10 hours, at least every 11 hours, at least every 12 hours, at least every 13 hours, at least every 14 hours, at least every 15 hours, at least every 16 hours, at least every 17 hours, at least every 18 hours, at least every 19 hours, at least every 20 hours, at least every 21 hours, at least every 22 hours, at least every 23 hours, or at least every day. [0179] Pharmaceutical compositions of the disclosure can be administered either acutely or chronically.
  • compositions of the disclosure can be administered as a single treatment or as a course of treatment.
  • Treatments can be administered once per day, twice per day, three times per day, in the morning, in the evening, before sleeping, or continuously throughout the day.
  • Treatments can be applied every day, every other day, every three days, twice weekly, once weekly, every other week, monthly, every six weeks, every other month, every three months, every six months, annually, every other year, every 5 years, or as required.
  • the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time.
  • the patient will have a drug holiday wherein the patient does not receive the drug or receives a reduced amount of the drug for a period of time.
  • a drug holiday can be, for example, between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • a drug holiday may be for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 12 months.
  • the dose reduction during a drug holiday can be, for example, by 10%- 100% of the original administered dose, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the dose reduction can be between 10% and 100%, between 20% and 80%, between 30% and 70%, between 50% and 90%, between 80% and 100% or between 90% and 100%.
  • Additional methods for administering the formulations described herein include, for example, limited to delivery via enteral routes including oral, gastric or duodenal feeding tube, rectal suppository, rectal enema, parenteral routes, injection, infusion, intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, intracameral, epidural, subcutaneous, inhalational, transdermal, transmucosal, sublingual, buccal, topical, epicutaneous, dermal, enemaear drops, intranasal, and vaginal administration.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository, rectal enema, parenteral routes, injection, infusion, intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperi
  • the compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • the length of the period of administration and/or the dosing amounts can be determined by a physician or any other type of clinician. The physician or clinician can observe the subject’s response to the administered compositions and adjust the dosing based on the subject’s performance. For example, dosing for subjects that show reduced effects in energy regulation can be increased to achieve desired results.
  • the combination therapies described herein can be administered together at the same time in the same route, or administered separately.
  • the components in the compositions can be administered using the same or different administration routes.
  • the disclosure also provides for methods of manufacturing the compositions described herein.
  • the manufacture of a composition described herein comprises mixing or combining two or more components.
  • the compositions can be combined or mixed with a pharmaceutically active or therapeutic agent, a carrier, and/or an excipient. Examples of such components are described herein.
  • the combined compositions can be formed into a unit dosage as tablets, capsules, gel capsules, slow-release tablets, or the like.
  • the composition is prepared such that a solid composition containing a substantially homogeneous mixture of the one or more components is achieved, such that the one or more components are dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • a unit dose may be packaged into a container to be transferred to the user.
  • a unit dose may be packaged in a tube, a jar, a box, a vial, a bag, a tray, a drum, a bottle, a syringe, or a can.
  • Another aspect of the disclosure provides for achieving desired effects in one or more subjects after administration of a combination composition described herein for a specified time period.
  • the beneficial effects of the compositions described herein can be observed after administration of the compositions to the subject for 1, 2, 3, 4, 6, 8, 10, 12, 24, or 52 weeks.
  • the combination therapies described herein may be administered by a combination treatment regimen.
  • a combination treatment regimen can encompass treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent.
  • the disclosure also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period.
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the combination therapy can provide a therapeutic advantage in view of the differential toxicity associated with the two treatment modalities.
  • treatment with CDK inhibitors such as those described herein can lead to a particular toxicity that is not seen with the anticancer agent, e.g., FLT3 inhibitor and vice versa.
  • this differential toxicity can permit each treatment to be administered at a dose at which said toxicities do not exist or are minimal, such that together the combination therapy provides a therapeutic dose while avoiding the toxicities of each of the constituents of the combination agents.
  • the compounds described herein or the pharmaceutically acceptable salts thereof, as well as combination therapies may be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein can be used as a prophylactic and may be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds described herein and compositions thereof may be administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein may be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • Use of the CDK inhibitor and the FLT3 inhibitor in the manufacture of a medicament [0193]
  • the present disclosure provides the use of a therapeutically effective amount of a CDK inhibitor of Formula Ib, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more anticancer agents in the manufacture of a medicament for treating a cancer, wherein the one or more anticancer agents comprise a FLT3 inhibitor.
  • the present disclosure provides the use of a therapeutically effective amount of a CDK inhibitor of Formula Ib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cancer, wherein the medicament is used for concurrent or sequential administration with a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP- 7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the one or more anticancer agents further comprise a therapeutically effective amount of a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the cancer is relapsed and/or refractory.
  • the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia. In one embodiment, the blood cancer is relapsed and/or refractory acute myeloid leukemia. [0198] In one embodiment, the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • the CDK inhibitor and the first anticancer agent are administered concurrently to a subject. In one embodiment, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject. [0200] In one embodiment, the CDK inhibitor and the first anticancer agent are administered sequentially to a subject. In one embodiment, the CDK inhibitor and the second anticancer agent are administered sequentially to a subject. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to a subject.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within 5 hours of each other. In one embodiment, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within 5 hours of each other. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within 5 hours of each other. [0204] In one embodiment, the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition. In one embodiment, the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day.
  • the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day.
  • Pharmaceutical combination comprising a CDK inhibitor and a FLT3 inhibitor
  • the present disclosure provides a pharmaceutical combination comprising a therapeutically effective amount of a CDK inhibitor of Formula Ib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP- 7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the pharmaceutical combination further comprises a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • the CDK inhibitor and the first anticancer agent are administered concurrently to a subject in need thereof.
  • the CDK inhibitor and the second anticancer agent are administered concurrently to a subject in need thereof.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject in need thereof.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to a subject in need thereof.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to a subject in need thereof.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to a subject in need thereof.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 5 hours of each other.
  • the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 5 hours of each other.
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 5 hours of each other.
  • the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition. [0216] In one embodiment, the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day. In one embodiment, the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day.
  • kits for the treatment of a cancer in a subject in need thereof, the kit comprising a therapeutically effective amount of a CDK inhibitor of Formula Ib or a pharmaceutically acceptable salt thereof, and a package insert comprising instructions directing the use of the CDK inhibitor in a combined treatment with a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP- 7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the pharmaceutical kit for the treatment of a cancer wherein the package insert further comprises directing the use of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent with a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of any either one thereof.
  • the cancer is relapsed and/or refractory.
  • the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia. In one embodiment, the blood cancer is relapsed and/or refractory acute myeloid leukemia. [0223] In one embodiment, the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent concurrently to the subject. In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent concurrently to the subject. In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent concurrently to the subject. [0225] In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject. In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject.
  • the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject. [0226] In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other. In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other. [0227] In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other. In one embodiment, the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other. [0228] In one embodiment, the package insert comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 5 hours of each other.
  • the package insert comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 5 hours of each other. In one embodiment, the package insert comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 5 hours of each other.
  • the pharmaceutical kit for the treatment of a cancer further comprises a therapeutically effective amount of the first anticancer agent, a therapeutically effective amount of the second anticancer agent, or a therapeutically effective amount of the first anticancer agent and a therapeutically effective amount of the second anticancer agent.
  • the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition.
  • the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition. [0231] In one embodiment, the CDK inhibitor and the first anticancer agent are administered to the subject daily, every other day, or every third day. In one embodiment, the CDK inhibitor and the second anticancer agent are administered to the subject daily, every other day, or every third day. In one embodiment, the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to the subject daily, every other day, or every third day. [0232] Clauses of the disclosure [0233] Clause 1.
  • a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 5 The method of any one of clauses 1 to 4, further comprising administering to the subject a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 7. The method of clause 6, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 8. The method of any one of clauses 1 to 7, wherein the cancer is relapsed and/or refractory.
  • Clause 9. The method of any one of clauses 1 to 8, wherein the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B- cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • Clause 14 The method of any one of clauses 5 to 13, wherein: the CDK inhibitor and the first anticancer agent are administered concurrently, the CDK inhibitor and the second anticancer agent are administered concurrently, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently.
  • Clause 15 The method of any one of clauses 5 to 13, wherein: the CDK inhibitor and the first anticancer agent are administered sequentially, the CDK inhibitor and the second anticancer agent are administered sequentially, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially. [0248] Clause 16.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib,
  • Clause 25 The pharmaceutical composition of any one of clauses 21 to 24, further comprising a second anticancer agent comprising a BCL-2 inhibitor.
  • Clause 26 The pharmaceutical composition of clause 25, wherein the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, TW-37, A-1210477, AT101, HA14-1, BAM7, S44563, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 27 The pharmaceutical composition of clause 26, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 28 A therapeutically effective amount of a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor for use in a method of treating a cancer.
  • Clause 29 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of clause 28, wherein the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX- 925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 32 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 28 to 31, further comprising a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor. [0265] Clause 33.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT- 737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1
  • Clause 34 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of clause 33, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 35 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 28 to 34, wherein the cancer is relapsed and/or refractory.
  • Clause 36 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 28 to 35, wherein the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lympho
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphocytic lymphoma
  • CLL
  • Clause 39 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of clause 38, wherein the blood cancer is relapsed and/or refractory acute myeloid leukemia.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • gastric cancer gastric cancer
  • the therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 32 to 40, wherein: the CDK inhibitor and the first anticancer agent are administered concurrently to a subject, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject.
  • the CDK inhibitor and the first anticancer agent are administered concurrently to a subject
  • the CDK inhibitor and the second anticancer agent are administered concurrently to a subject
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject.
  • the CDK inhibitor and the first anticancer agent are administered sequentially to a subject
  • the CDK inhibitor and the second anticancer agent are administered sequentially to a subject
  • the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to a subject.
  • Clause 44 The therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of clause 42, wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • the therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 32 to 41, wherein: the CDK inhibitor and first anticancer agent are co-formulated in a pharmaceutical composition, the CDK inhibitor and the second anticancer agent are co- formulated in a pharmaceutical composition, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition. [0279] Clause 47.
  • the therapeutically effective amount of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent for the use of any one of clauses 32 to 46, wherein: the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day, the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day. [0280] Clause 48.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 52 The use of any one of clauses 48 to 51, further comprising a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A- 1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 54 The use of clause 53, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 55 The use of any one of clauses 48 to 54, wherein the cancer is relapsed and/or refractory
  • Clause 56 The use of any one of clauses 58 to 55, wherein the cancer is a blood cancer.
  • Clause 57 The use of any one of clauses 58 to 55, wherein the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B- cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma [0290] Clause 58.
  • AML acute myeloid leukemia
  • CML chronic myeloid
  • any one of clauses 48 to 55 wherein the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • gastric cancer gastric cancer.
  • Clause 66 The use of any one of clauses 52 to 61, wherein: the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition, the CDK inhibitor and the second anticancer agent are co-formulated in a pharmaceutical composition, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition.
  • Clause 67 The use of any one of clauses 48 to 66, wherein: the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day, the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day. [0300] Clause 68.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutini
  • Clause 72 The use of any one of clause 68 to 71, further comprising a second anticancer agent comprising a BCL-2 inhibitor [0305] Clause 73.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A- 1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 74 The use of clause 73, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 75 The use of any one of clauses 68 to 74, wherein the cancer is relapsed and/or refractory.
  • Clause 76 The use of any one of clauses 68 to 75, wherein the cancer is a blood cancer.
  • Clause 77 Clause 77.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B- cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymph
  • Clause 78 The use of clause 77, wherein the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia [0311] Clause 79. The use of clause 78, wherein the blood cancer is relapsed and/or refractory acute myeloid leukemia. [0312] Clause 80.
  • any one of clauses 68 to 75 wherein the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • gastric cancer gastric cancer
  • any one of clauses 72 to 80 wherein: the CDK inhibitor and the first anticancer agent are administered concurrently to a subject, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject.
  • Clause 82 The use of any one of clauses 72 to 80, wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to a subject, the CDK inhibitor and the second anticancer agent are administered sequentially to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to a subject.
  • clause 82 wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other. [0316] Clause 84.
  • clause 82 wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other. [0317] Clause 85.
  • any one of clauses 72 to 86 wherein: the CDK inhibitor and the first anticancer agent are administered to a subject daily, every other day, or every third day, the CDK inhibitor and the second anticancer agent are administered to a subject daily, every other day, or every third day, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered to a subject daily, every other day, or every third day.
  • Clause 88 A pharmaceutical combination comprising a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • any one of clauses 88 to 90 wherein the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutini
  • Clause 92 The pharmaceutical combination of any one of clause 88 to 91, wherein further comprising a second anticancer agent comprising a BCL-2 inhibitor.
  • Clause 93 The pharmaceutical combination of clause 92, wherein the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 94 The pharmaceutical combination of clause 93, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 95 The pharmaceutical combination of any one of clauses 92 to 94, wherein: the CDK inhibitor and the first anticancer agent are administered concurrently to a subject in need thereof, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject in need thereof, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject in need thereof..
  • Clause 96 Clause 96.
  • a pharmaceutical kit for the treatment of a cancer in a subject in need thereof comprising a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: Ib, or a pharmaceutically acceptable salt thereof, and a package insert comprising instructions directing the use of the CDK inhibitor in a combined treatment with a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • a CDK inhibitor represented by Formula Ib: Ib or a pharmaceutically acceptable salt thereof
  • a package insert comprising instructions directing the use of the CDK inhibitor in a combined treatment with a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • Clause 105 The pharmaceutical kit for the treatment of a cancer of any one of clauses 102 to 104, wherein the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX- 925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof
  • Clause 106 The pharmaceutical kit for the treatment of a cancer of any one of clauses 102 to 105, wherein the package insert further comprises directing the use of the CDK inhibitor and the therapeutically effective amount of the first anticancer agent with a therapeutically effective amount of a second anticancer agent comprising a BCL-2 inhibitor.
  • Clause 107 Clause 107.
  • the pharmaceutical kit for the treatment of a cancer of clause 106 wherein the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI- 77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof.
  • the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-
  • AML acute myeloid leukemia
  • Clause 112. The pharmaceutical kit for the treatment of a cancer of clause 111, wherein the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia.
  • Clause 113. The pharmaceutical kit for the treatment of a cancer of clause 112, wherein the blood cancer is relapsed and/or refractory acute myeloid leukemia.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • gastric cancer gastric cancer
  • Clause 116 Clause 116.
  • the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject
  • the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject
  • the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject.
  • the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other
  • the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other.
  • the package insert further comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the package insert further comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other
  • the package insert further comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours of each other.
  • Clause 119 The pharmaceutical kit for the treatment of a cancer of clause 118, wherein: the package insert comprises instructions for administering the CDK inhibitor and the first anticancer agent sequentially to the subject within about 5 hours of each other, the package insert comprises instructions for administering the CDK inhibitor and the second anticancer agent sequentially to the subject within about 5 hours of each other, or the package insert comprises instructions for administering the CDK inhibitor, the first anticancer agent, and the second anticancer agent sequentially to the subject within about 5 hours of each other [0352] Clause 120.
  • Clause 121 The pharmaceutical kit for the treatment of a cancer of clause 120, wherein: the CDK inhibitor and the first anticancer agent are co-formulated in a pharmaceutical composition, the CDK inhibitor and the second anticancer agent are co- formulated in a pharmaceutical composition, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are co-formulated in a pharmaceutical composition
  • Clause 122 Clause 122.
  • a pharmaceutical composition comprising a therapeutically effective amount of a CDK inhibitor represented by Formula Ib: , or a pharmaceutically acceptable salt thereof, wherein the composition is used for concurrent or sequential administration with a therapeutically effective amount of a first anticancer agent comprising a FLT3 inhibitor.
  • Clause 124 The pharmaceutical composition of clause 123, wherein the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • Clause 125 The pharmaceutical composition of clause 124, wherein the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • any one of clauses 123 to 125 wherein the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutin
  • Clause 127 The pharmaceutical composition any one of clauses 123 to 126, further comprising a second anticancer agent comprising a BCL-2 inhibitor [0360] Clause 128.
  • Clause 129 The pharmaceutical composition of clause 128, wherein the BCL-2 inhibitor is navitoclax, venetoclax, or a pharmaceutically acceptable salt of either one thereof.
  • Clause 130 The pharmaceutical composition of any one of clauses 127 to 129, wherein: the CDK inhibitor and the first anticancer agent are administered concurrently to a subject, the CDK inhibitor and the second anticancer agent are administered concurrently to a subject, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered concurrently to a subject.
  • the pharmaceutical composition of clause 131 wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or within about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other. [0365] Clause 133.
  • Clause 137 A pharmaceutical composition for use in the treatment of a cancer, comprising a therapeutically effective amount of a CDK inhibitor represented by Formula Ib:
  • Clause 138 The pharmaceutical composition of clause 137, wherein the FLT3 inhibitor inhibits wild type FLT3, mutated FLT3, or both wild type FLT3 and mutated FLT3.
  • Clause 139 The pharmaceutical composition of clause 138, wherein the mutated FLT3 is FLT3-ITD or FLT3-TKD.
  • any one of clauses 137 to 139 wherein the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutinib, KW-2449, crenolanib, gilteritinib, quizartinib, CHIR-258, IMC-EB10, XL 999, GTP 14564, AG1295, AG1296, CEP-5214, CEP-7055, FLX-925, G-749, PLX3397, E6201, AKN-028, famitinib, nilotinib, and DCC-2036, or a pharmaceutically acceptable salt of any one thereof.
  • the FLT3 inhibitor is selected from sunitinib, midostaurin, lestaurtinib, sorafenib, donafenib, ponatinib, tandutin
  • Clause 141 The pharmaceutical composition any one of clauses 137 to 140, further comprising a second anticancer agent comprising a BCL-2 inhibitor.
  • Clause 142 The pharmaceutical composition of clause 141, wherein the BCL-2 inhibitor is selected from navitoclax, venetoclax, A-1155463, A-1331852, ABT-737, obatoclax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sabutoclax, UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, Bax inhibitor peptide V5, Bax inhibitor peptide P5, Bax channel blocker, and ARRY 520 trifluoroacetate, or a pharmaceutically acceptable salt of any one thereof [0375] Clause 143.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), chronic lymphocytic leukemia (CLL), mast cell leukemia (MCL), lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and multiple myeloma [0379] Clause 147.
  • AML acute myeloid leukemia
  • CML chronic myeloid
  • any one of clauses 137 to 144 wherein the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • the cancer is selected from pancreatic cancer, intestinal cancer, myelodysplastic syndrome, kidney cancer, liver cancer, thyroid cancer, renal cell carcinoma, head and neck cancer, pharyngeal cancer, glioblastoma, colorectal cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, triple negative breast cancer (TNBC), urothelial carcinoma, and gastric cancer.
  • TNBC triple negative breast cancer
  • gastric cancer gastric cancer
  • the pharmaceutical composition of clause 151 wherein: the CDK inhibitor and the first anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, the CDK inhibitor and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other, or the CDK inhibitor, the first anticancer agent, and the second anticancer agent are administered sequentially to the subject within about 12, about 24, about 36, or about 72 hours, or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days of each other. [0385] Clause 153.
  • Example 1 Combination Profiling of MEI-522 (Voruciclib) in 20 Cancer Cell Lines
  • the aim of this study was to determine the activity of MEI Pharma’s lead compound MEI-522 (Voruciclib) across a panel of 20 cancer cell lines utilizing Horizon Discovery’s High Throughput Screening platform. Growth inhibition was determined using a 72-hour CellTiter- Glo®2.0 proliferation assay. Results have been supplied as both Chalice Analyzer files (.mcc) and raw luminescence data.
  • Voruciclib single agent activity [0393] Fig.1. Cell line response to MEI-522 (Voruciclib) at 72 hours ranked by Response Area. Single agent activity of MEI-522 (Voruciclib) was extracted from the combination dose matrices. Cell line responses are ranked by median response.
  • PROTOCOL [0394] The method for High Throughput Screen is described below. The endpoint readout of this assay is based upon quantitation of ATP as an indicator of viable cells. [0396] Cell lines that have been preserved in liquid nitrogen are thawed and expanded in growth media (see Appendix I). Once cells have reached expected doubling times, screening begins.
  • Cells are seeded in 25 ⁇ l of growth media in black 384-well tissue culture treated plates at 500 cells per well (as noted in Analyzer). Cells are equilibrated in assay plates via centrifugation and placed at 37 °C 5% CO 2 for twenty-four hours before treatment. At the time of treatment, a set of assay plates (which do not receive treatment) are collected and ATP levels are measured by adding CellTiter-Glo 2.0 (Promega) and luminescence read on Envision plate readers (Perkin Elmer). Compounds are transferred to assay plates using and Echo acoustic liquid handling system.25 nl of each compound was added at the appropriate concentration for all combination dose points. Therefore, final assay volume would be 25.05 ⁇ l.
  • GI Growth Inhibition
  • the GI percentages are calculated by applying the following test and equation: If T ⁇ V_0 : 100*(1-(T-V_0)/V_0 ) If T ⁇ V_0 : 100*(1-(T-V_0)/(V-V_0)) where T is the signal measure for a test article, V is the untreated/vehicle-treated control measure, and Vo is the untreated/vehicle control measure at time zero (also colloquially referred as T0 plates).
  • T is the signal measure for a test article
  • V is the untreated/vehicle-treated control measure
  • Vo is the untreated/vehicle control measure at time zero (also colloquially referred as T0 plates).
  • This formula is derived from the Growth Inhibition calculation used in the National Cancer Institute’s NCI-60 high throughput screen. For the purposes of this disclosure, all data analysis was performed in Growth Inhibition (except where noted).
  • a GI reading of 0% represents no growth inhibition and would occur in instances where the T reading at 3 days is comparable to the V reading at the respective time-period.
  • a GI of 100% represents complete growth inhibition (cytostasis) and in this case cells treated with compound for 3 days would have the same endpoint reading as T0 control cells.
  • a GI of 200% represents complete death (cytotoxicity) of all cells in the culture well and in this case the T reading at 3 days will be lower than the T0 control (values near or at zero). See Figs. 2A-2B below.
  • Figs.2A-2B Dose Response curve representations of cytostatic vs cytotoxic compound activity.
  • Inhibition is also provided as a measure of cell viability.
  • Combination Effect Reference Models [0404] Combination effects can be most readily characterized by comparing each data point to that of a combination reference model that was derived from single agent curves (refer to single agent curve fitting section below).
  • the Highest Single Agent is a simple reference model where the expected combination effect is the maximum of the single agent responses at corresponding concentrations;
  • the Bliss Independence model represents the statistical expectation for independent competing inhibitors;
  • the Loewe Additivity model represents the expected response if both agents are actually the same compound and is the most generally accepted reference for synergy. Both HSA and Bliss are easily calculated, however determining Loewe Additivity is experimentally demanding and requires well-sampled single agent dose curves, data interpolation and iterative root finding for computation of the Loewe additive response surface.
  • Highest Single Agent Model is based simply on the intuition that if a combination’s effect exceeds the effect level of each of its constituents, there must be some combination interaction. This model is generally selected for the analysis of combinations where there is a limited dose range or ratio available.
  • Empirically derived combination matrices are compared to their respective HSA additivity models constructed from experimentally collected single agent dose response curves. Summation of this excess additivity across the dose response matrix is referred to HSA Volume. Positive HSA Volume suggests potential synergy, while negative HSA Volume suggests potential antagonism.
  • HSA model is a simple reference model where the expected combination effect is the maximum of the single agent response at corresponding concentrations. Hence, experimental noise of the single agent activity (typically observed below GI 30-50 %) can contribute to artificially high HSA Volume Score thereby, adversely affecting the accurate assessment of combination activates.
  • Bliss Independence Model corresponds to multiplicative probabilities for effects in growth measures and is the preferred reference for synergy in some contexts, especially genetics.
  • Bliss boosting which models boosts in efficacy at high concentrations different from what the single agents can achieve, is adapted from the Bliss independence model that corresponds to a multiplicative effect in growth measures.
  • I Bliss (C X ,C Y ) I X + I Y – I X I Y
  • CX,Y are the concentrations of the X and Y compound
  • IX and IY are inhibitions of the single agents at C X,Y .
  • the Bliss volume score represents the statistical expectation for independent competing inhibitors. Bliss Independence has often been favoured because it can be directly calculated from minimally sampled experiments without single agent response curve interpolation or iterative root finding.
  • Loewe Additivity Model [0413] The Loewe additivity model is dose-based and applies only to the activity levels achieved by the single agents.
  • Loewe Volume is used to assess the overall magnitude of the combination interaction in excess of the Loewe additivity model. Loewe Volume is particularly useful when distinguishing synergistic increases in a phenotypic activity (positive Loewe Volume) versus synergistic antagonisms (negative Loewe Volume). When antagonisms are observed, the Loewe Volume should be assessed to examine if there is any correlation between antagonism and a particular drug target-activity or cellular genotype. This model defines additivity as a non-synergistic combination interaction where the combination dose matrix surface should be indistinguishable from either drug crossed with itself.
  • Synergy Score log f X log f Y ⁇ max(0,I data )(I data – I Loewe ) [0416]
  • the fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of all untreated/vehicle-treated control wells.
  • the Synergy Score equation integrates the experimentally-observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe model for additivity. Additional terms in the Synergy Score equation (above) are used to normalize for various dilution factors used for individual agents and to allow for comparison of synergy scores across an entire experiment.
  • each vertical concentration C Y is held fixed while a bisection algorithm is used to identify the horizontal concentration CX in combination with that vertical dose that gives the chosen effect level in the response surface Z(CX,CY). These concentrations are then connected by linear interpolation to generate the isobologram display. For synergistic interactions, the isobologram contour falls below the additivity threshold and approaches the origin, and an antagonistic interaction would lie above the additivity threshold. The error bars represent the uncertainty arising from the individual data points used to generate the isobologram.
  • CI values in the range of 0.5 - 0.7 are typical for in vitro measurements of current clinical combinations.
  • the CI error ( ⁇ CI) is calculated using standard error propagation through the CI calculation based on the isobologram errors.
  • the Best CI is reported from the many CI values calculated for each ICut crossing combination. Among all the measured CI values, the one with the largest single-to- noise level (1-CI)/ ⁇ CI is reported as the Best CI.
  • Best CI Level is the effect level from which the CI is calculated.
  • Example 2 Comparative In Vivo Oncology (CIVO) injects multiple drugs and/or drug combinations simultaneously in microdose quantities directly into a patient’s tumor.
  • the device delivers trackable drug “columns.”
  • Co-injection with CIVO GLO enables injection site identification. Drugs interact with the tumor within the patient and then the tumor is surgically removed.
  • the tumor is processed by sectioning cross-wise to the drug columns and placed onto slides for staining.
  • Proprietary software and developed assays allow for deep profiling around each injection site to quantify and highlight immune profiles, cell signaling activations, tumor microenvironment (TME) impact, responder hypotheses, and/or drug combination potential.
  • CIVO can be used to study the combination of voruciclib with a FLT3 inhibitor or the combination of voruciclib with a FLT3 inhibitor and a BCL-2 inhibitor in tumors.
  • Example 3 Monotherapy Phase 1 Studies in Solid Tumors
  • 2 weeks on /1 week off schedule 75 to 850 mg; 29 pts in dose escalation / expansion at 600 mg cohorts; 41% disease control rate; 1 PR and 8 SD lasting 2 to 6 months.
  • Daily continuously schedule 75 to 500 mg; 39 pts in dose escalation / expansion at 350 mg cohorts; 31% disease control rate ; 12 SD lasting a median of 15 weeks.
  • Safety profile most common AEs involved GI tract; no evidence of myelosuppression.
  • Figs.4A-4C illustrate CR in a Patient with Pulmonary Metastases; Fig.4A: baseline CT scan; Fig.4B: 2 months after starting the trial, radiological CR based on official radiological report; Fig.4C: 14 months after starting the trial, patient remained on trial for 12 months only, and CR remained durable for 14 months.
  • Example 5 Leveraging CDK9 Regulation of MCL1: Phase 1 Study in R/R B-Cell Malignancies and AML [0427] Study population: Relapsed/Refractory B-cell malignancies; Relapsed/Refractory AML; Dose escalation with standard 3+3 design. [0428] Endpoints: Safety and tolerability, Pharmacokinetics, Biologic correlative studies (BH3 profiling, MCL-1 expression, molecular mutations analysis), Response rates.
  • Voruciclib single agent dose escalation 50 mg > 100 mg > 150 mg > 200 mg.
  • Phase 1 Study in Hematologic Malignancies 24 pts treated in 3 dose levels, 10 AML and 14 B-cell malignancies, No GI toxicity or neutropenia at doses studied,
  • Favorable PK profile across all voruciclib studies (Half life 24-28 hours supports once-a-day dosing, Dose proportional Cmax and AUC; High volume of distribution indicates broad entry into tissues); Doses of 150-200 mg may achieve plasma concentrations sufficient to inhibit molecular target.
  • Voruciclib Shows Preferential Tumor Accumulation in Preclinical Model
  • Figs.5A- 5D HCT-116 CRC cell xenograft in SCID mice.8 mice per time point (2 control, 6 orally dosed with voruciclib at 100 mpk). Animals were randomized into 2 groups when tumors reached 100 mm diameter. Group A assigned single dosing. Group B assigned 5 day dosing. 8 mice per time point (2 control, 6 orally dosed with voruciclib at 100 mpk). Drug concentration was measured in tumor and plasma after last dose at the following time points: 0, 4, 8, 24, 48, 72 hrs.
  • the accumulation index of voruciclib in tumors after 5 days of repeat dosing was 1.45. Concentration of voruciclib in plasma is in units of ⁇ g/ml and in ⁇ g/g for tumors. Voruciclib fold increase in tumors relative to plasma are indicated. [0432] Higher levels (>5 fold) of voruciclib were found in tumor at 8 hours compared to 24 hours post dosing. Negligible levels of voruciclib were observed in the plasma at 24 hours. Moreover, tumor to plasma ratio was found to be > 5 fold at both time points.
  • Example 7 Evidence of Biologic Activity in AML [0433] Differentiation syndrome seen in 5 pts (50%) (Increased WBC without increased in blasts, bone pain, pulmonary symptoms; Response to corticosteroids). [0434] Differentiation syndrome with ATRA, IDHi, and other AML targeted therapies.
  • Example 8 Voruciclib Dosing Regimen [0435] PK data for 2 weeks of daily dosing followed by 1 week without dosing in a 21-day cycle is presented Table 3, and PK data for daily dosing continuously is presented in Table 4. Table 3: Descriptive Statistics (Mean ⁇ Std. Dev) of PK Parameters of Voruciclib on Day 1 and Day 13 112
  • Voruciclib half life is designated as t1/2 in the tables (expressed in hours). Steady state (i.e., Day 13-15) half-life ranges from 16 hours to 358 hours, with an average of 24 to 48 hours. There is interpatient variability, explaining the outlier values. When the drug is stopped, it takes ⁇ 5 half-lives, or 5-10 days for the drug to be eliminated from the plasma. [00405] Voruciclib volume of distribution is designated as Vz/F (expressed in liters). Steady state (i.e., Day 13-15) volume of distribution ranges from 185 L to 982 L, with an average of ⁇ 300 L (and outlier values).
  • Voruciclib volume of distribution is ⁇ 60 times larger than the blood volume, indicating broad distribution into tissues.
  • the drug takes an additional 3 days to clear from the tissue after it clears the plasma.
  • voruciclib dosing on a 14 days on / 14 days off schedule can prevent tissue toxicity.
  • such dosing regimen can match the dosing schedule of a combination drug.
  • Example 9 Combination of voruciclib with a FLT3 inhibitor, and optionally with a BCL-2 inhibitor, in AML organoid models Study Rationale [00407] There is no standard of care for the relapsed/salvage setting in AML, and this remains an area of high unmet need for the relapsed/refractory patient population. Patients with FLT3 mutations are commonly treated with FLT3 inhibitors.
  • AML and autologous immune cells are cultured in the liquid part of the 3D BM model.
  • This micro-scalable architecture ensures large-scale application with primary samples for rapid drug response tests, aiming to evaluate efficacy and hematological toxicity.
  • Aim [00409] The study assesses the potential of voruciclib to combine with FLT3 inhibitors in FLT3 mutant AML organoid models, which provides data to support future in vivo murine model work and inform clinical development. Voruciclib is tested in combination with other drugs against a panel of AML patient derived 3D BM models.
  • a dose-response curve of AML cell lines to voruciclib is determined in the 3D BM model. To this aim, a panel of AML cell lines harboring FLT3 activating mutations are used. Similarly, voruciclib, voruciclib/Ven, and FLT3i treatments are tested in the 3D model, based on evidence from the literature.

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Abstract

La divulgation concerne des polythérapies destinées au traitement du cancer. La divulgation concerne des polythérapies d'inhibiteurs de CDK, par exemple, un inhibiteur de CDK représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci conjointement avec un inhibiteur de FLT3. La divulgation concerne en outre des polythérapies d'inhibiteurs de CDK, par exemple, un inhibiteur de CDK de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, conjointement avec un inhibiteur de FLT3 et un inhibiteur de BCL-2.
PCT/US2024/016215 2023-02-16 2024-02-16 Combinaison d'un inhibiteur de cdk et d'un inhibiteur de flt3 destinée au traitement du cancer Ceased WO2024173833A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170121323A1 (en) * 2014-07-26 2017-05-04 Sunshine Lake Pharma Co., Ltd. 2-amino-pyrido[2,3-d]pyrimidin-7(8h)-one derivatives as cdk inhibitors and uses thereof
WO2022109307A1 (fr) * 2020-11-19 2022-05-27 Mei Pharma, Inc. Traitement de cancers mutants de kras
US20220168273A1 (en) * 2014-05-28 2022-06-02 Piramal Enterprises Limited Pharmaceutical Combination for the Treatment of Cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220168273A1 (en) * 2014-05-28 2022-06-02 Piramal Enterprises Limited Pharmaceutical Combination for the Treatment of Cancer
US20170121323A1 (en) * 2014-07-26 2017-05-04 Sunshine Lake Pharma Co., Ltd. 2-amino-pyrido[2,3-d]pyrimidin-7(8h)-one derivatives as cdk inhibitors and uses thereof
WO2022109307A1 (fr) * 2020-11-19 2022-05-27 Mei Pharma, Inc. Traitement de cancers mutants de kras

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