Venetoclax Dosing Regimen for Use in Combination with a CYP3A Inhibitor and Azacitidine to Treat Myelodysplastic Syndromes

Abstract

The invention described herein relates to a therapeutic dosing regimen comprising administering venetoclax in combination with azacitidine and a CYP3A inhibitor for the treatment of myelodysplastic syndromes (MDS).

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 201,743, filed May 11, 2021, the disclosure of which is incorporated by reference in its entirety herein.

[0002] The present invention relates to a method of treating myelodysplastic syndrome (MDS) in a human subject, comprising administering venetoclax in combination with azacitidine to a subject, where the subject is also receiving a CYP3A inhibitor. [Background technology]

[0003] Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders with significant morbidity and high mortality. These syndromes are characterized by ineffective hematopoiesis, which manifests clinically as cytopenias and as transformation to acute myeloid leukemia (secondary or sAML) at various rates. Although approximately one-third of MDS patients subsequently develop AML, MDS is not considered to be the primary form of AML. The main cause of death in MDS patients is not AML transformation but bone marrow failure, particularly neutropenia leading to infections, including pulmonary hemorrhagic shock, or thrombocytopenia leading to bleeding.

[0004] Approximately half (45%) of MDS patients present with high MDS risk (International Prognostic Scoring System (IPSS) composite score >1.5) and have a median survival of less than 1 year with best supportive care. The only curative treatment for high-risk MDS is allogeneic stem cell or bone marrow transplantation. However, not all patients are eligible for this intensive treatment approach. When bone marrow transplantation is not possible, patients are usually treated with hypomethylating agents such as azacitidine. Currently, azacitidine is the only drug shown to extend survival in treatment-naive high-risk MDS, but overall results need to be improved.

[0005] Venetoclax is an oral small molecule inhibitor of B-cell lymphoma 2 (BCL-2) that rapidly induces multiple hallmarks of apoptotic cell death. Venetoclax has been investigated in clinical oncology studies as a monotherapy and in combination with various compounds for the treatment of a number of hematological malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, the dosing regimen used in the first clinical trial of venetoclax in MDS produced adverse side effects in certain patients. For example, two subjects developed fatal sepsis in the setting of severe neutropenia. Thus, there is a need in the art for dosing regimens for MDS patients who experience certain side effects. In addition, venetoclax can be administered with CYP3A inhibitors. Thus, there is a need in the art for dosing regimens for MDS with venetoclax and azacitidine when co-administered with strong or moderate CYP3A inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0006] (Brief Summary of the Invention) The present disclosure relates to methods of treating myelodysplastic syndromes in human subjects, and in some embodiments, more particularly to methods of treating treatment-naïve high-risk myelodysplastic syndromes. [Means for solving the problem]

[0007] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject comprises administering a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days of a 28 day dosing cycle, or a daily dose of 75 mg / m 2 for 7 days of a 28-day dosing cycle and a CYP3A inhibitor to a human subject. In certain embodiments, the myelodysplastic syndrome is a treatment-naive high-risk myelodysplastic syndrome.

[0008] In certain embodiments, the daily dose of venetoclax is 200 mg and the CYP3A inhibitor is a moderate CYP3A inhibitor. In other embodiments, the daily dose of venetoclax is 100 mg and the CYP3A inhibitor is a strong CYP3A inhibitor. In yet other embodiments, the daily dose of venetoclax is 70 mg and the CYP3A inhibitor is posaconazole.

[0009] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 for 7 days of a 28-day dosing cycle and a CYP3A inhibitor to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor, 100 mg when administered in combination with a strong CYP3A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole.

[0010] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 of azacitidine for 7 days of a 28-day dosing cycle and a CYP3A inhibitor are administered to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor and 50 mg when administered in combination with a strong CYP3A inhibitor.

[0011] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 of azacitidine for 7 days of a 28-day dosing cycle and a CYP3A inhibitor are administered to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor and 100 mg when administered in combination with a strong CYP3A inhibitor. [Brief description of the drawings]

[0012] [Figure 1] Plot of mean absolute neutrophil counts by study day cycle. Number of observations are shown in Table 11. [Diagram 2] Plot of mean platelet counts by study day cycle. Number of observations are shown in Table 11. [Figure 3A] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3B] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3C] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3D] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3E] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3F]3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 4A] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. [Figure 4B] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. [Figure 4C] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure relates to a method of treating treatment-naïve, higher-risk myelodysplastic syndrome (MDS) in a human subject, comprising administering to the subject venetoclax in combination with azacitidine.

[0014] While venetoclax has been administered to patients with AML with a prior history of MDS (sAML), this is the first disclosure to evaluate venetoclax in combination with azacitidine in subjects with MDS, and more specifically in subjects with treatment-naïve high-risk MDS, with the dosing regimen modified accordingly for subjects who are also receiving a strong or moderate CYP3A inhibitor. Apart from the specific dosing modifications disclosed herein for subjects receiving a strong or moderate CYP3A inhibitor while receiving venetoclax, other significant differences for the administration of venetoclax in combination with azacitidine for MDS compared to AML include a reduction in the duration of venetoclax administration from 28 days to 14 days in the 28-day cycle for MDS, as well as the absence of any dosing increase in subjects with MDS.

[0015] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and a CYP3A inhibitor, to a human subject.

[0016] "Venetoclax" is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. Venetoclax is a selective Bcl-2 inhibitor approved for adult patients with CLL and adult patients with newly diagnosed AML who are 75 years of age or older or who are ineligible for intensive induction chemotherapy.

[0017] Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. It is supplied in a sterile form to be reconstituted as a suspension for subcutaneous injection or as a solution that is further diluted for intravenous infusion.

[0018] Strong and moderate CYP3A inhibitors are drugs that increase the AUC of a sensitive index substrate in the CYP3A metabolic pathway by ≧5-fold and ≧2 to <5-fold, respectively.

[0019] Examples of strong CYP3A inhibitors include boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole.

[0020] Examples of moderate CYP3A inhibitors include aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil.

[0021] Posaconazole is available as a concentrated liquid to be diluted before intravenous administration, as delayed-release tablets, or as a suspension for oral administration.

[0022] The term "AE" as used herein refers to adverse event.

[0023] The term "AML" as used herein refers to acute myeloid leukemia.

[0024] The term "ANC" as used herein refers to absolute neutrophil count.

[0025] The term "CLL" as used herein refers to chronic lymphocytic leukemia.

[0026] The term "CML" as used herein refers to chronic myeloid leukemia.

[0027] The term "CMML" as used herein refers to chronic myelomonocytic leukemia.

[0028] The term "CR" as used herein refers to complete response.

[0029] The term "CTC" as used herein refers to Common Terminology Criteria.

[0030] The term "ECOG" as used herein refers to the Eastern Cooperative Oncology Group.

[0031] The term "G-CSF" as used herein refers to granulocyte colony stimulating factor.

[0032] The term "HRQoL" as used herein refers to health-related quality of life.

[0033] The term "HMA" as used herein refers to a hypomethylating agent.

[0034] The term "HR-MDS" as used herein refers to high-risk myelodysplastic syndromes.

[0035] The term "IPSS" as used herein refers to the International Prognostic Scoring System.

[0036] The term "IPSS-R" as used herein refers to the Revised International Prognostic Scoring System.

[0037] The term "JMML" as used herein refers to juvenile myelomonocytic leukemia.

[0038] The term "mCR" as used herein refers to complete bone marrow remission.

[0039] The term "MDS" as used herein refers to myelodysplastic syndromes.

[0040] The term "MPN" as used herein refers to myeloproliferative neoplasms.

[0041] The term "OS" as used herein refers to overall survival.

[0042] The term "PR" as used herein refers to partial response.

[0043] The term "RAEB" as used herein refers to refractory anemia with excess blasts.

[0044] The term "sAML" as used herein refers to secondary acute myeloid leukemia.

[0045] The term "SE1" as used herein refers to Safety Expansion Cohort 1.

[0046] The term "SE2" as used herein refers to safety expansion cohort 2.

[0047] The term "TEAE" as used herein refers to treatment-emergent adverse events.

[0048] The term "tMDS" as used herein refers to treatment-related or therapy-related myelodysplastic syndrome.

[0049] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and a CYP3A inhibitor, to a human subject.

[0050] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 200 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 for 7 days of a 28 day dosing cycle and a moderate CYP3A inhibitor to a human subject. In certain embodiments, the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil.

[0051] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 200 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2for 7 days of a 28-day dosing cycle, and a moderate CYP3A inhibitor selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam and verapamil, and venetoclax is administered daily on days 1 through 14 of the dosing cycle.

[0052] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 200 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle and a moderate CYP3A inhibitor to a human subject, wherein the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil, and the venetoclax is administered every 14 days from day 1 of the dosing cycle, and the 7 days of the daily dose of azacitidine are within the first 9 days of the 28-day dosing cycle. In some embodiments, the azacitidine is administered intravenously. In some embodiments, the azacitidine is administered subcutaneously.

[0053] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2of azacitidine for 7 days of a 28-day dosing cycle and a strong CYP3A inhibitor are administered to a human subject. In some embodiments, the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole. In some embodiments, the daily dose of venetoclax is 100 mg. In some embodiments, the daily dose of venetoclax is 50 mg.

[0054] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 for 7 days of a 28-day dosing cycle, and a strong CYP3A inhibitor selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole, and venetoclax is administered daily on days 1 through 14 of the dosing cycle.

[0055] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 for 7 days of a 28-day dosing cycle and a strong CYP3A inhibitor selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole; and wherein the venetoclax is administered daily on days 1 through 14 of the dosing cycle, and wherein the daily dose of azacitidine is within the first 9 days of the 28-day dosing cycle. In some embodiments, azacitidine is administered intravenously. In some embodiments, azacitidine is administered subcutaneously.

[0056] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 50 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2for 7 days of a 28-day dosing cycle, and a strong CYP3A inhibitor selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole, and venetoclax is administered daily on days 1 through 14 of the dosing cycle. In some embodiments, the daily dose of azacitidine is within the first 9 days of a 28-day administration cycle. In some embodiments, azacitidine is administered intravenously. In some embodiments, azacitidine is administered subcutaneously.

[0057] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 70 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and posaconazole, to a human subject.

[0058] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 70 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and posaconazole administered to a human subject, wherein venetoclax is administered daily on days 1 through 14 of the dosing cycle.

[0059] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 70 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 for 7 days of a 28-day dosing cycle and posaconazole to a human subject, wherein venetoclax is administered daily on days 1 through 14 of the dosing cycle, and the 7 days of daily doses of azacitidine are within the first 9 days of the 28-day dosing cycle. In some embodiments, the azacitidine is administered intravenously. In some embodiments, the azacitidine is administered subcutaneously.

[0060] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and posaconazole, to a human subject.

[0061] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2 of azacitidine for 7 days of a 28-day dosing cycle, and posaconazole administered to a human subject, wherein venetoclax is administered daily on days 1 through 14 of the dosing cycle.

[0062] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of 100 mg of venetoclax for 14 days of a 28-day dosing cycle, or a daily dose of 75 mg / m 2for 7 days of a 28-day dosing cycle and posaconazole to a human subject, wherein venetoclax is administered daily on days 1 through 14 of the dosing cycle, and the 7 days of daily doses of azacitidine are within the first 9 days of the 28-day dosing cycle. In some embodiments, the azacitidine is administered intravenously. In some embodiments, the azacitidine is administered subcutaneously.

[0063] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 for 7 days of a 28 day dosing cycle and a CYP3A inhibitor to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor, 100 mg when administered in combination with a strong CYP3A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole. In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome.

[0064] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2for 7 days of a 28-day dosing cycle and a CYP3A inhibitor, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor, 100 mg when administered in combination with a strong CYP3A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole, and the moderate CYP3A inhibitors include aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isomerase inhibitor, and cyclosporine. The CYP3A inhibitor is selected from the group consisting of buconazole, fluvoxamine, imatinib, tofisopam, and verapamil, and the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole. In some embodiments, venetoclax is administered daily on days 1 through 14 of a dosing cycle. In other embodiments, the 7 days of the daily dose of azacitidine are within the first 9 days of a 28-day dosing cycle. In some embodiments, azacitidine is administered intravenously. In some embodiments, azacitidine is administered subcutaneously.

[0065] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2for 7 days of a 28 day dosing cycle and a CYP3A inhibitor to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor, and 50 mg or 70 mg or 100 mg when administered in combination with a strong CYP3A inhibitor. In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome.

[0066] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 of azacitidine for 7 days of a 28-day dosing cycle and a CYP3A inhibitor are administered to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor and 50 mg when administered in combination with a strong CYP3A inhibitor.

[0067] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2for 7 days of a 28-day dosing cycle, and a CYP3A inhibitor, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor and 50 mg when administered in combination with a strong CYP3A inhibitor, the moderate CYP3A inhibitors being aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofiso The CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole. In some embodiments, venetoclax is administered daily on days 1 through 14 of a dosing cycle. In other embodiments, the 7 days of the daily dose of azacitidine are within the first 9 days of a 28-day dosing cycle. In some embodiments, azacitidine is administered intravenously. In some embodiments, the azacitidine is administered subcutaneously.

[0068] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 of azacitidine for 7 days of a 28-day dosing cycle and a CYP3A inhibitor are administered to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor and 100 mg when administered in combination with a strong CYP3A inhibitor.

[0069] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method includes administering a daily dose of venetoclax at a daily dose of 75 mg / m for 14 days of a 28-day dosing cycle. 2 for 7 days of a 28-day dosing cycle, and a CYP3A inhibitor to a human subject, wherein the daily dose of venetoclax is 200 mg when administered in combination with a moderate CYP3A inhibitor, and 70 mg or 100 mg when administered in combination with a strong CYP3A inhibitor, and the moderate CYP3A inhibitors include aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, The strong CYP3A inhibitor is selected from the group consisting of tofisopam and verapamil, and the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole. In some embodiments, venetoclax is administered daily on days 1 through 14 of a dosing cycle. In other embodiments, the 7 days of the daily dose of azacitidine are within the first 9 days of a 28-day dosing cycle. In some embodiments, azacitidine is administered intravenously. In some embodiments, azacitidine is administered subcutaneously. EXAMPLES

[0070] In order that the invention described herein may be more fully understood, the following examples are set forth.

[0071] A multicenter, nonrandomized Phase 1b study was initiated in adults with previously untreated high-risk MDS, defined as IPSS risk classification intermediate-2 or high (IPSS pooled score ≥ 1.5). The initial protocol randomized patients to one of three treatment arms: venetoclax 800 mg + azacitidine, venetoclax 400 mg + azacitidine, and azacitidine monotherapy. In the initial protocol, venetoclax was administered on days 1 through 28 of each 28-day cycle, with dosing initiated according to the cycle 1 escalation dosing. This dosing schedule resulted in two patients developing fatal sepsis in the setting of severe neutropenia, after which the study was placed on partial clinical hold and enrollment was temporarily halted. The partial clinical hold was lifted based on a revised protocol, which ultimately resulted in a low incidence of infections and cases of leukopenia.

[0072] Test Design

[0073] Inclusion criteria Subjects aged 18 years or older with a diagnosis of treatment-naïve IPSS intermediate-2 or high-risk myelodysplastic syndrome with ECOG ≤ 2 were enrolled. In this study, inclusion criteria included:

[0074] 1. Subjects must be ≥ 18 years of age.

[0075] 2. The target is: a. Have an International Prognostic Scoring System (IPSS) risk classification of intermediate-2 or high (i.e., a minimum IPSS score of 1.5) or a Revised IPSS (IPSS-R) classification of intermediate, high, or very high (score >3); and b. Presence of <20% myeloblasts per bone marrow biopsy / aspirate; Must have a documented diagnosis of previously untreated de novo MDS.

[0076] 3. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≦2.

[0077] According to the International Prognostic Scoring System, patients with myelodysplastic syndromes are divided into two main risk groups: low risk and high risk. High-risk myelodysplastic syndromes, as used herein, are defined as International Prognostic Scoring System (IPSS) risk classification intermediate-2 or high (i.e., minimum IPSS score of 1.5), or revised IPSS (IPSS-R) classification intermediate, high, or very high (combined score >3).

[0078] [Table 1]

[0079] Subjects with high-risk MDS are classified into intermediate, high, and very high in the revised International Prognostic Scoring System (IPSS-R) classification. This patient population roughly corresponds to the IPSS intermediate-2 and high-risk groups, and the World Health Organization (WHO) histological subtypes of refractory anemia with excess blasts (RAEB)-1 and RAEB-2. The IPSS-R is also currently considered to be a well-validated assessment tool to identify patients who are generally considered clinically appropriate to undergo aggressive treatment. The revised International Prognostic Scoring System (IPSS-R) is shown in Table 2 and includes a high-precision classification of cytogenetic abnormalities, more specific cutoffs for bone marrow blast count and cytopenias, weighted by their severity. The revised International Prognostic Scoring System risk groups for myelodysplastic syndromes are defined based on the integrated score. The integrated score is calculated as the sum of the blast score, cytogenetic score, hemoglobin score, platelet score, and absolute neutrophil count score.

[0080] [Table 2]

[0081] ECOG performance status was assessed using the criteria in Table 3.

[0082] [Table 3]

[0083] Main Exclusion Criteria 1. Subject has previously been treated for MDS.

[0084] 2. Subject has previously been treated with a BH3 mimetic.

[0085] 3. The target is: MDS with IPSS low or intermediate-1 risk classification (IPSS combined score < 1.5), b. Treatment-related MDS (t-MDS), C. MDS that has evolved from a previously existing myeloproliferative neoplasm (MPN), d. MDS / MPN, including chronic myelomonocytic leukemia (CMML), atypical chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), and unclassified MDS / MPN have a previously untreated diagnosis other than de novo MDS, including

[0086] 4. Subject has received a strong or moderate CYP3A inducer within 7 days prior to the first dose of study drug.

[0087] 5. Subjects enrolled in dose escalation cohorts, except for the safety expansion cohort, have received a strong or moderate CYP3A inhibitor within 3 days prior to the first dose of study drug.

[0088] Azacitidine 75 mg / m 2(daily intravenously or subcutaneously) for 7 days and venetoclax at 400 mg for 14 days of each 28-day cycle. In both cohorts, dose modifications in cycle 1 were not recommended. Dose modifications in subsequent cycles were prescribed for adverse events. In safety expansion cohort 1 (SE1), venetoclax was initially reduced due to significant neutrophil or platelet toxicity. Per protocol dose reductions were 33% for azacitidine or 50% for venetoclax during the 14 days of each cycle. In subsequent cycles, the duration of venetoclax could be shortened to 9 days in each cycle. In safety expansion cohort 2 (SE2), dose modification guidelines were revised to initially reduce the azacitidine dose (initially 50 mg / m 2 , followed by 36 mg / m 2 ), followed by a 7-day duration taper (venetoclax 400 mg) with each cycle of venetoclax was recommended. The impact of each dose modification strategy on safety and efficacy in SE1 and SE2 was compared. Worsening from baseline in treatment-emergent adverse event grades was analyzed by cycle. Response was assessed using IWG 2006 criteria. Analyses included all subjects who received ≥1 dose of study drug.

[0089] [Table 4]

[0090] When venetoclax was coadministered with a moderate or strong CYP3A inhibitor, the venetoclax dose was reduced as shown in Table 5.

[0091] [Table 5]

[0092] Treatment dose reduction may be indicated following prior interruption of treatment, delay in starting the next cycle, occurrence of adverse events with hematological toxicity, significant reduction in neutrophils or significant reduction in platelets. A stepwise azacitidine dose modification was performed, followed by an adjustment of venetoclax treatment from 14 days to 7 days in the final step after performing all azacitidine dose modification steps. Venetoclax and azacitidine were resumed on the same day after any delay or interruption in treatment.

[0093] result: Baseline characteristics of SE1 and SE2 are shown in Table 6 . Twenty-two subjects with SE1 and 21 subjects with SE2 were compared with a median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) months, respectively, as shown in Table 7 .

[0094] [Table 6]

[0095] [Table 7]

[0096] A summary of adverse events in >20% of subjects is shown in Table 8. Similar frequencies of grade ≥3 hematological treatment-emergent adverse events (approximate %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%), and thrombocytopenia (32% and 38%). Infections (59% and 38%) and leukopenia (36% and 19%) were more frequent in SE1 than in SE2.

[0097] [Table 8]

[0098] The deterioration of treatment-emergent adverse event grade from baseline was analyzed for each cycle. As shown in Figures 3A-3F and 4A-4C, the progression of adverse events remains low after the first few cycles, e.g., cycles 1 and 2. Figures 3A-3F are hematological toxicity showing the number of patients with a deterioration of Common Terminology Criteria grade from baseline per cycle. Figures 4A-4C are gastrointestinal toxicity showing the number of patients with a deterioration of Common Terminology Criteria grade from baseline per cycle.

[0099] Response rates were the same for SE1 and SE2, with 86% of subjects in both SE1 and SE2 having a complete response (CR) or marrow complete response (mCR), as shown in Table 9. In subjects with mCR, hematologic improvement occurred in 50% of SE1 subjects and 46% of SE2 subjects.

[0100] [Table 9]

[0101] A summary of cycle delays is shown in Table 10. Cycle delays were comparable for SE1 and SE2, with SE1 being slightly longer in duration in early cycles.

[0102] [Table 10]

[0103] The mean absolute neutrophil and platelet counts are shown in Figures 1 and 2, respectively. The observed number of counts by day of the study cycle for both absolute neutrophil and platelet counts is shown in Table 11.

[0104] [Table 11]

[0105] 86% of both SE1 and SE2 patients had a complete response or bone marrow complete response.

[0106] Venetoclax dose modifications in patients receiving moderate or strong CYP3A inhibitors were used in subsequent clinical trials as shown in Tables 12 and 13.

[0107] [Table 12]

[0108] [Table 13]

[0109] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the invention, which is defined solely by the appended claims and equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including those related to the method of use of the invention, can be made without departing from the spirit and scope of the invention. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A pharmaceutical composition comprising venetoclax, The pharmaceutical composition is for use in combination with azacitidine and / or a CYP3A inhibitor in a method for treating myelodysplastic syndrome in a human subject, The methods include administering venetoclax at a daily dose of 200 mg, 100 mg, 70 mg or 50 mg for 14 days of a 28-day dosing cycle, or at a daily dose of 75 mg / m ２ for 7 days of a 28 day dosing cycle and a CYP3A inhibitor to a human subject.

2. The pharmaceutical composition according to claim 1, wherein the myelodysplastic syndrome is a treatment-naïve high-risk myelodysplastic syndrome.

3. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 200 mg and the CYP3A inhibitor is a moderate CYP3A inhibitor.

4. 4. The pharmaceutical composition of claim 3, wherein the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam and verapamil.

5. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 100 mg and the CYP3A inhibitor is a strong CYP3A inhibitor.

6. 6. The pharmaceutical composition of claim 5, wherein the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir combination, elvitegravir / ritonavir combination, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir combination, nefazodone, nelfinavir, paritaprevir / ritonavir combination, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir combination, troleandomycin and voriconazole.

7. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 100 mg.

8. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 50 mg.

9. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 70 mg and the CYP3A inhibitor is posaconazole.

10. 2. The pharmaceutical composition of claim 1, wherein the daily dose of venetoclax is 100 mg and the CYP3A inhibitor is posaconazole.

11. A pharmaceutical composition comprising venetoclax, The pharmaceutical composition is for use in combination with azacitidine and / or a CYP3A inhibitor in a method for treating myelodysplastic syndrome in a human subject, The method comprises administering a daily dose of venetoclax at a daily dose of 75 mg / m2 for 14 days of a 28-day dosing cycle. ２ for 7 days of a 28 day dosing cycle, and a CYP3A inhibitor, The daily dose of venetoclax is a. 200 mg when administered in combination with a moderate CYP3A inhibitor; b. 100 mg when administered in combination with a strong CYP3A inhibitor other than posaconazole; c. 70 mg when administered in combination with posaconazole Pharmaceutical compositions.

12. The pharmaceutical composition according to claim 11, wherein the myelodysplastic syndrome is a treatment-naïve high-risk myelodysplastic syndrome.

13. the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam and verapamil; 12. The pharmaceutical composition of claim 11, wherein the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir combination, elvitegravir / ritonavir combination, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir combination, nefazodone, nelfinavir, paritaprevir / ritonavir combination, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir combination, troleandomycin and voriconazole.

14. 12. The pharmaceutical composition of claim 11, wherein venetoclax is administered daily on days 1 through 14 of an administration cycle.

15. 12. The pharmaceutical composition of claim 11, wherein the 7 days of the daily dose of azacitidine are within the first 9 days of a 28 day dosing cycle.

16. 12. The pharmaceutical composition of claim 11, wherein the azacitidine is administered intravenously.

17. The pharmaceutical composition of claim 11, wherein the azacitidine is administered subcutaneously.

18. A pharmaceutical composition comprising venetoclax, The pharmaceutical composition is for use in combination with azacitidine and / or a CYP3A inhibitor in a method for treating myelodysplastic syndrome in a human subject, The method comprises administering a daily dose of venetoclax at a daily dose of 75 mg / m2 for 14 days of a 28-day dosing cycle. ２ for 7 days of a 28 day dosing cycle, and a CYP3A inhibitor, The daily dose of venetoclax is a. 200 mg when administered in combination with a moderate CYP3A inhibitor; b. 50 mg, 70 mg, or 100 mg when administered in combination with a strong CYP3A inhibitor Pharmaceutical compositions.

19. The pharmaceutical composition according to claim 18, wherein the myelodysplastic syndrome is a treatment-naïve high-risk myelodysplastic syndrome.

20. The daily dose of venetoclax is a. 200 mg when administered in combination with a moderate CYP3A inhibitor; b) 50 mg when administered in combination with a strong CYP3A inhibitor.

21. the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam and verapamil; 21. The pharmaceutical composition of claim 20, wherein the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir combination, elvitegravir / ritonavir combination, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir combination, nefazodone, nelfinavir, paritaprevir / ritonavir combination, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir combination, troleandomycin and voriconazole.

22. The daily dose of venetoclax is a. 200 mg when administered in combination with a moderate CYP3A inhibitor; b) 100 mg when administered in combination with a strong CYP3A inhibitor.

23. the moderate CYP3A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam and verapamil; 23. The pharmaceutical composition of claim 22, wherein the strong CYP3A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir combination, elvitegravir / ritonavir combination, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir / ritonavir combination, nefazodone, nelfinavir, paritaprevir / ritonavir combination, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir / ritonavir combination, troleandomycin and voriconazole.

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