WO2022240786A1 - Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine - Google Patents

Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine Download PDF

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WO2022240786A1
WO2022240786A1 PCT/US2022/028429 US2022028429W WO2022240786A1 WO 2022240786 A1 WO2022240786 A1 WO 2022240786A1 US 2022028429 W US2022028429 W US 2022028429W WO 2022240786 A1 WO2022240786 A1 WO 2022240786A1
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count
nadir
baseline
absolute neutrophil
human subject
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French (fr)
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John Hayslip
Steve H. KYE
William B. AINSWORTH
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AbbVie Inc
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AbbVie Inc
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Priority to CN202280048997.0A priority Critical patent/CN117642161A/zh
Priority to BR112023023677A priority patent/BR112023023677A2/pt
Priority to AU2022273023A priority patent/AU2022273023A1/en
Priority to EP22808145.1A priority patent/EP4337183A4/en
Priority to IL308321A priority patent/IL308321A/en
Priority to KR1020237042682A priority patent/KR20240006659A/ko
Priority to MX2023013364A priority patent/MX2023013364A/es
Priority to JP2023569885A priority patent/JP2024517318A/ja
Priority to CA3219760A priority patent/CA3219760A1/en
Publication of WO2022240786A1 publication Critical patent/WO2022240786A1/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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

Definitions

  • MDS patients Approximately half (45%) of MDS patients present with higher-risk MDS risk (International Prognostic Scoring System (IPSS) overall score > 1.5) and have a median survival less than one year with best supportive care.
  • the only curative treatment for higher-risk MDS is an allogeneic stem cell or bone marrow transplantation. However, not all patients are eligible for this intensive treatment approach. If bone marrow transplantation is not possible, patients are typically treated with hypomethylating agents such as azacitidine. Currently, azacitidine is the only drug shown to prolong survival in treatment-naive higher-risk MDS, however, overall outcomes need to be improved.
  • Venetoclax is an oral small molecule inhibitor of B-cell lymphoma 2 (BCL-2) that rapidly induces multiple hallmarks of apoptotic cell death.
  • BCL-2 B-cell lymphoma 2
  • Venetoclax is being investigated in clinical oncology studies as a monotherapy and in combination with a variety of compounds for the treatment of a number of hematologic malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).
  • CLL chronic lymphocytic leukemia
  • AML acute myeloid leukemia
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine of 75 mg/m 2 is reduced to ⁇ 50% but no less than 33% during a next 28 day dosing cycle.
  • the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 x 10 9 /L, or a baseline platelet count of ⁇ 75 c 10 9 /L.
  • a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to 50% during a next 28 day dosing cycle.
  • the human subject has a baseline absolute neutrophil count of > 1.5 x 10 9 /L, a baseline white blood cell count of > 3 c 10 9 /L, or a baseline platelet count of > 75 x 10 9 /L.
  • FIG. l is a plot of the mean value of the absolute neutrophil count versus study day cycle. The number of observations is shown in Table 11.
  • FIG. 2 is a plot of the mean value of the platelet count versus study day cycle. The number of observations is shown in Table 11.
  • FIGs. 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with worsening common terminology criteria grade over baseline per cycle.
  • FIG. 4A is diarrhea.
  • FIG. 4B is vomiting.
  • FIG. 4C is nausea.
  • venetoclax has been administered to patients with AML who had a prior history of MDS (sAML), herein is the first disclosure evaluating venetoclax in combination with azacitidine in subjects with MDS, more specifically, in those subjects with treatment-naive higher-risk MDS, in which the dosing regimen is modified to account for subjects who have developed hematological toxicities after beginning treatment.
  • the dosing regimen is modified to account for subjects who have developed hematological toxicities after beginning treatment.
  • other significant differences between dosing venetoclax in combination with azacitidine for MDS versus AML include reducing the duration of venetoclax dosing from 28 to 14 days in the 28 day cycle for MDS, as well the lack of any dosing ramp up for subjects with MDS.
  • Azacitidine is 4-amino-l-P-D-ribofuranosyl-s-triazin-2(lH)-one. Azacitidine is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion.
  • AE refers to adverse event
  • AML refers to acute myeloid leukemia.
  • CMML chronic myelomonocytic leukemia
  • CTC CTC
  • ECOG Eastern Cooperative Oncology Group
  • G-CSF refers to granulocyte colony-stimulating factor
  • HR-MDS refers to higher risk myelodysplastic syndromes.
  • IPSS International Prognostic Scoring System
  • IVS-R Revised International Prognostic Scoring System
  • MPN myeloproliferative neoplasm
  • SE1 Safety Expansion Cohort 1.
  • SE2 Safety Expansion Cohort 2.
  • No improvement in cell line differentiation refers to the lack of clear improvement in cell differentiation at the time of the next cycle. For example, the percentage of mature granulocytes is lower and the absolute neutrophil count is lower than at onset of the dosing cycle.
  • a method for treating myelodysplastic syndromes in a human subject is provided, wherein the myelodysplastic syndromes are treatment-naive higher- risk myelodysplastic syndromes.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 x 10 9 /L; no improvement in cell line differentiation; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of > 50% reduction, a white blood cell count nadir of > 50% reduction, and a platelet count nadir of > 50% reduction; the
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 x 10 9 /L; no improvement in cell line differentiation; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of > 50% reduction, a white blood cell count nadir of > 50% reduction, and a platelet count nadir of > 50% reduction; the
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 x 10 9 /L; no improvement in cell line differentiation; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of > 50% reduction, a white blood cell count nadir of > 50% reduction, and a platelet count nadir of > 50% reduction; the
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day.
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 x 10 9 /L; no improvement in cell line differentiation; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of > 50% reduction, a white blood cell count nadir of > 50% reduction, and a platelet count nadir of > 50% reduction; the
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine of 75 mg/m 2 is reduced to ⁇ 50% during but no less than 33% a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 c 10 9 /L; wherein the human subject has no improvement in cell line differentiation; and wherein the human subject has at least one condition selected from the group consisting of: an
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine of 75 mg/m 2 is reduced to ⁇ 50% but no less than 33% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 c 10 9 /L; wherein the human subject has no improvement in cell line differentiation; and wherein the human subject has at least one condition selected from the group consisting of: an absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine of 75 mg/m 2 is reduced to ⁇ 50% but no less than 33% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 c 10 9 /L; wherein the human subject has no improvement in cell line differentiation; wherein the human subject has at least one condition selected from the group consisting of: an absolute neutrophil count
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine of 75 mg/m 2 is reduced to ⁇ 50% but no less than 33% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of ⁇ 1.5 c 10 9 /L, a baseline white blood cell count of ⁇ 3 c 10 9 /L, or a baseline platelet count of ⁇ 75 c 10 9 /L; wherein the human subject has no improvement in cell line differentiation; wherein the human subject has at least one condition selected from the group consisting of: an absolute neutrophil count
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day. [0071] In certain embodiments, a method for treating myelodysplastic syndromes in a human subject is provided, wherein the myelodysplastic syndromes are treatment-naive higher- risk myelodysplastic syndromes.
  • the method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has: a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.5 c 10 9 /L; and a platelet count nadir of ⁇ 50 x 10 9 /L; the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 67% but no less than 50% during a next 28 day dosing cycle.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.5 c 10 9 /L; and a platelet count nadir of ⁇ 50 x 10 9 /L; ; the daily dose of azacitidine is
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.5 c 10 9 /L; and a platelet count nadir of ⁇ 50 x 10 9 /L; ; the daily dose of azacitidine is
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein if the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; and at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.5 c 10 9 /L; and a platelet count nadir of ⁇ 50 x 10 9 /L; ; the daily dose of azacitidine is
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of >
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to 50% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 x 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; and wherein the human subject has at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.0 x 10 9 /L; and a platelet count nadir of ⁇ 50 c 10 9 /L.
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. [0082] In certain embodiments, a method for treating myelodysplastic syndromes in a human subject is provided, wherein the myelodysplastic syndromes are treatment-naive higher- risk myelodysplastic syndromes.
  • the method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to 50% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 x 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.0 x 10 9 /L; and a platelet count nadir of ⁇ 50 c 10 9 /L; and wherein the human subject has prior to a start of the next 28 day dosing cycle, at least one condition selected from the group consisting of:
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to 50% during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, a baseline white blood cell count of > 3 x 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of ⁇ 1.0 x 10 9 /
  • the azacitidine is administered intravenously. In other aspects, the azacitidine is administered subcutaneously. In yet other aspects, the method further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day. In still other aspects, the method further comprises a delay prior to the next 28 day dosing cycle of > 1 day; and further comprises a delay prior to the subsequent 28 day dosing cycle of > 1 day.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 50 mg/m 2 but no less than 36 mg/m 2 during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has a previous response of complete remission, partial remission, or marrow complete remission at the beginning of a prior dosing cycle; and wherein the human subject has at least one of a condition selected from the group consisting of: an absolute neutrophil count nadir of
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 50 mg/m 2 but no less than 36 mg/m 2 during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has a previous response of complete remission, partial remission, or marrow complete remission at the beginning of a prior dosing cycle; and wherein
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 50 mg/m 2 but no less than 36 mg/m 2 during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has a previous response of complete remission, partial remission, or marrow complete remission at the beginning of a prior dosing cycle; wherein the
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 50 mg/m 2 but no less than 36 mg/m 2 during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has a previous response of complete remission, partial remission, or marrow complete remission at the beginning of a prior dosing cycle; wherein the
  • ⁇ 50 x 10 9 /L wherein the baseline platelet was > 100 c 10 9 /L, a platelet count nadir of ⁇ 50 %; wherein the baseline platelet was ⁇ 100 c 10 9 /L; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to 50 mg/m 2 ; and wherein the daily dose of azacitidine is reduced from 50 mg/m 2 to 36 mg/m 2 in a successive 28 day dosing cycle.
  • a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days in a 28 day dosing cycle, and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle; wherein the daily dose of azacitidine is reduced from 75 mg/m 2 to ⁇ 50 mg/m 2 but no less than 36 mg/m 2 during a next 28 day dosing cycle; wherein the human subject has a baseline absolute neutrophil count of > 1.5 c 10 9 /L, or a baseline platelet count of > 75 c 10 9 /L; wherein the human subject has a previous response of complete remission, partial remission, or marrow complete remission at the beginning of a prior dosing cycle; wherein the
  • the myelodysplastic syndromes are treatment-naive higher-risk myelodysplastic syndromes.
  • the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg/m 2 .
  • the dosing cycle is 28 days.
  • the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle.
  • the daily dose of 400 mg of venetoclax is reduced from 14 to 7 days in a further subsequent 28 day dosing cycle if the human subject has prior to a start of the further subsequent 28 day dosing cycle, at least one condition selected from the group consisting of: a next absolute neutrophil count of ⁇ 25% above the absolute neutrophil count nadir and relative to a difference of the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count of ⁇ 25% above the white blood cell count nadir and relative to a difference of the baseline white blood cell count and the white blood cell count nadir, and a next platelet count of ⁇ 25% above the platelet count nadir and relative to a difference of the baseline platelet count and the platelet count nadir.
  • the azacitidine is administered intravenously. In yet other aspects, the azacitidine is administered subcutaneously.
  • the myelodysplastic syndromes are treatment-naive higher-risk myelodysplastic syndromes.
  • the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg/m 2 .
  • the dosing cycle is 28 days.
  • the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle and a daily dose of 75 mg/m 2 of azacitidine for 7 days in the 28 day dosing cycle.
  • the daily dose of 400 mg of venetoclax is reduced from 14 to 7 days in a further subsequent 28 day dosing cycle if the human subject has prior to a start of the further subsequent 28 day dosing cycle, at least one condition selected from the group consisting of: a next absolute neutrophil count of ⁇ 25% above the absolute neutrophil count nadir and relative to a difference of the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count of ⁇ 25% above the white blood cell count nadir and relative to a difference of the baseline white blood cell count and the white blood cell count nadir, and a next platelet count of ⁇ 25% above the platelet count nadir and relative to a difference of the baseline platelet count and the platelet count nadir.
  • the azacitidine is administered intravenously. In yet other aspects, the azacitidine is administered subcutaneously.
  • the daily dose of 400 mg of venetoclax is reduced from 14 to 7 days in a further subsequent 28 day dosing cycle if the human subject has prior to a start of the further subsequent 28 day dosing cycle, at least one condition selected from the group consisting of: a next absolute neutrophil count of ⁇ 25% above the absolute neutrophil count nadir and relative to a difference of the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count of ⁇ 25% above the white blood cell count nadir and relative to a difference of the baseline white blood cell count and the white blood cell count nadir, and a next platelet count of ⁇ 25% above the platelet count nadir and relative to a difference of the baseline platelet count and the platelet count nadir.
  • the azacitidine is administered intravenously. In yet other aspects, the azacitidine is administered subcutaneously.
  • a method for treating myelodysplastic syndromes in a human subject comprises (a) obtaining a baseline absolute neutrophil count, a baseline white blood cell count, and a baseline platelet count from the human subject,
  • the daily dose of 400 mg of venetoclax is reduced from 14 to 7 days in a further subsequent 28 day dosing cycle if the human subject has prior to a start of the further subsequent 28 day dosing cycle, at least one condition selected from the group consisting of: a next absolute neutrophil count of ⁇ 25% above the absolute neutrophil count nadir and relative to a difference of the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count of ⁇ 25% above the white blood cell count nadir and relative to a difference of the baseline white blood cell count and the white blood cell count nadir, and a next platelet count of ⁇ 25% above the platelet count nadir and relative to a difference of the baseline platelet count and the platelet count nadir.
  • the azacitidine is administered intravenously. In yet other aspects, the azacitidine is administered subcutaneously.
  • the original protocol randomized patients into 1 of 3 treatment groups: venetoclax 800 mg + azacitidine, venetoclax 400 mg + azacitidine, and azacitidine monotherapy.
  • venetoclax was administered on Days 1 through 28 of each 28-day-cycle and dosing was initiated according to a ramp-up dosing schedule in Cycle 1. With this dosing schedule, 2 patients developed fatal sepsis in the setting of severe neutropenia, after which the study was placed on partial clinical hold and enrollment was suspended. The partial clinical hold was lifted based on a revised protocol, which ultimately resulted in a lower incidence of infections and leukopenia events.
  • Subj ect must be > 18 years of age.
  • Subject has a diagnosis other than previously untreated de novo MDS, including: a. MDS with IPSS risk categories Low or Int-1 (overall IPSS score ⁇ 1.5) b. Therapy-related MDS (t-MDS) c. MDS evolving from a pre-existing myeloproliferative neoplasm (MPN) d. MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
  • CMML chronic myelomonocytic leukemia
  • CML chronic myeloid leukemia
  • JMML juvenile myelomonocytic leukemia
  • unclassifiable MDS/MPN unclassifiable MDS/MPN.
  • Subject has received strong or moderate CYP3 A inducers within 7 days prior to the first dose of study drug.
  • subjects who initiate a cycle of treatment with absolute neutrophil count ⁇ 1.5 X 10 9 / L and platelets V 75 X 10 9 / L and have a previous response of complete remission, partial remission, or marrow complete remission may require dose reduction, if subsequent absolute neutrophil count nadir ⁇ 0.500 c 10 9 / L, or platelets nadir ⁇ 50 x 10 9 / L, if baseline was > 100 c 10 9 / L, or platelets ⁇ 50% if baseline was ⁇ 100 c 10 9 / L.
  • Table 7 Summary of Adverse Events a Includes death, life-threatening, requiring hospitalization or surgical intervention, persistent/significant disability. b SE1: abdominal pain, diverticular perforation, and gastroesophageal reflux disease; SE2: nausea, pancreatitis, vomiting, and gastrointestinal hemorrhage
  • FIGs. 3A-3F and FIGs. 4A-4C Worsening of treatment-emergent adverse events grades from baseline was analyzed by cycle. As shown in FIGs. 3A-3F and FIGs. 4A-4C, adverse event progression remains low after the first few cycles, such as cycles 1 and 2.
  • FIGs. 3A-3F are hematologic toxicity showing the number of patients with worsening common terminology criteria grade over baseline per cycle.
  • FIGs. 4A-4C are gastrointestinal toxicity showing the number of patients with worsening common terminology criteria grade over baseline per cycle.

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PCT/US2022/028429 2021-05-11 2022-05-10 Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine Ceased WO2022240786A1 (en)

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CN202280048997.0A CN117642161A (zh) 2021-05-11 2022-05-10 与阿扎胞苷联合用于治疗骨髓增生异常综合征的维奈托克给药方案
BR112023023677A BR112023023677A2 (pt) 2021-05-11 2022-05-10 Regimes de dosagem de venetoclax para o uso no tratamento de síndromes mielodisplásicas em combinação com azacitidina
AU2022273023A AU2022273023A1 (en) 2021-05-11 2022-05-10 Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine
EP22808145.1A EP4337183A4 (en) 2021-05-11 2022-05-10 Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine
IL308321A IL308321A (en) 2021-05-11 2022-05-10 Venetoclax dosing regimens for use in treating myelodysplastic syndromes in combination with azacitidine
KR1020237042682A KR20240006659A (ko) 2021-05-11 2022-05-10 아자시티딘과 병용한 골수형성이상 증후군의 치료시 사용하기 위한 베네토클락스 투약 용법
MX2023013364A MX2023013364A (es) 2021-05-11 2022-05-10 Regimenes de dosificacion de venetoclax para usarse en el tratamiento de los sindromes mielodisplasicos en combinacion con azacitidina.
JP2023569885A JP2024517318A (ja) 2021-05-11 2022-05-10 アザシチジンと組み合わせて骨髄異形成症候群の処置に使用されるベネトクラクス投与レジメン
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160235779A1 (en) * 2015-02-17 2016-08-18 Cantex Pharmaceuticals, Inc. Treatment of cancers and hematopoietic stem cell disorders privileged by cxcl12-cxcr4 interaction
WO2020257671A1 (en) * 2019-06-20 2020-12-24 Celgene Corporation Azacitidine in combination with venetoclax, gilteritinib, midostaurin or other compounds for treating leukemia or myelodysplastic syndrome
US20210023237A1 (en) * 2019-04-29 2021-01-28 Immunogen, Inc. Therapeutic combinations comprising anti-cd123 immunoconjugates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021037933A1 (en) * 2019-08-28 2021-03-04 Astrazeneca Ab Combination of azd2811 nanoparticles, 5-azacitidine and venetoclax for use in the treatment of cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160235779A1 (en) * 2015-02-17 2016-08-18 Cantex Pharmaceuticals, Inc. Treatment of cancers and hematopoietic stem cell disorders privileged by cxcl12-cxcr4 interaction
US20210023237A1 (en) * 2019-04-29 2021-01-28 Immunogen, Inc. Therapeutic combinations comprising anti-cd123 immunoconjugates
WO2020257671A1 (en) * 2019-06-20 2020-12-24 Celgene Corporation Azacitidine in combination with venetoclax, gilteritinib, midostaurin or other compounds for treating leukemia or myelodysplastic syndrome

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BACHAR SAMRA, MARINA KONOPLEVA, ALESSANDRO ISIDORI, NAVAL DAVER, COURTNEY DINARDO: "Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions", FRONTIERS IN ONCOLOGY, vol. 10, 1 November 2020 (2020-11-01), XP055758842, DOI: 10.3389/fonc.2020.562558 *
DINARDO C D; JONAS B A; PULLARKAT V; THIRMAN M J; GARCIA J S; WEI A H; KONOPLEVA M; DOEHNER H; LETAI A; FENAUX P; KOLLER E; HAVELA: "Azacitidine and Venetoclax in Previously Untreated AcuteMyeloidLeukemia", THE NEW ENGLAND JOURNAL OF MEDICINE, MASSACHUSETTS MEDICAL SOCIETY, US, vol. 383, no. 7, 13 August 2020 (2020-08-13), US , pages 617 - 629, XP009525543, ISSN: 0028-4793, DOI: 10.1056/NEJMoa2012971 *
See also references of EP4337183A4 *

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