Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • 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
  • A61K31/13—Amines
  • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• • 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
  • A61K31/275—Nitriles; Isonitriles
  • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and 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
  • A61K31/33—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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • A61K31/33—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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • 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
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention relates to methods for treating myelodysplastic syndromes (MDS) in a human subject comprising administering to the subject venetoclax in combination with azacitidine, where the subject is also receiving a CYP3 A inhibitor.
• MDS myelodysplastic syndromes
• MDS Myelodysplastic Syndromes
• 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
• venetoclax may be dosed with CYP3 A inhibitors. Therefore, there is a need in the art for dosing regimens for MDS with venetoclax and azacitidine when co-dosed with strong or moderate CYP3 A inhibitors.
• the present disclosure relates to methods for treating myelodysplastic syndromes in a human subject, and in some aspects, more specifically treatment-naive higher-risk myelodysplastic syndromes.
• a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor.
• the myelodysplastic syndromes are treatment-naive higher-risk myelodysplastic syndromes.
• the daily dose of venetoclax is 200 mg and the CYP3 A inhibitor is a moderate CYP3 A inhibitor. In other embodiments, the daily dose of venetoclax is 100 mg and the CYP3 A inhibitor is a strong CYP3 A inhibitor. In yet other embodiments, the daily dose of venetoclax is 70 mg and the CYP3 A inhibitor is posaconazole.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, 100 mg when administered in combination with a strong CYP3 A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 50 mg when administered in combination with a strong CYP3 A inhibitor.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 100 mg when administered in combination with a strong CYP3 A inhibitor.
• 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. 3A-3F are bar graphs of hematologic toxicity showing the number of patients with worsening common terminology criteria grade over baseline per cycle.
• FIG. 3A is anemia.
• FIG. 3B is febrile neutropenia.
• FIG. 3C is leukopenia.
• FIG. 3D is neutropenia.
• FIG. 3E is thrombocytopenia.
• FIG. 3F is infections.
• 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.
• This present disclosure relates to methods for treating treatment-naive higher-risk myelodysplastic syndromes (MDS) in a human subject comprising administering to the subject venetoclax in combination with azacitidine.
• MDS myelodysplastic syndromes
• 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 are also receiving a strong or moderate CYP3 A inhibitor.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor.
• Venetoclax is 4-(4- ⁇ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yljmethyl Jpiperazin-1 -yl)-A f -( J 3nitro-4-[(tetrahydro-2//-pyran-4- yl methyl )amino]phenyl ⁇ sulfonyl)-2-( 1 //-pyrrol o[2, 3 -/>]pyridin5-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 or older, or who are ineligible for intensive induction chemotherapy.
• 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.
• Strong and moderate CYP3 A inhibitors are drugs that increase the AUC of sensitive index substrates of the CYP3 A metabolic pathway >5-fold and >2 to ⁇ 5-fold, respectively.
• Examples of strong CYP3 A inhibitors include boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir, elvitegravir/ritonavir, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir, nefazodone, nelfmavir, paritaprevir/ritonavir combinations, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, and voriconazole.
• moderate CYP3 A inhibitors include aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil.
• Posaconazole is available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.
• AE refers to adverse event
• AML refers to acute myeloid leukemia.
• ANC neutrophil count
• CLL chronic lymphocytic leukemia
• CML chronic myeloid leukemia
• CMML chronic myelomonocytic leukemia
• CR refers to complete remission
• CTC CTC
• ECOG Eastern Cooperative Oncology Group
• G-CSF refers to granulocyte colony-stimulating factor
• HRQoL refers to health-related quality of life.
• HMAs refers to hypomethylating agents.
• HR-MDS refers to higher risk myelodysplastic syndromes.
• IVS International Prognostic Scoring System.
• IPSS-R Revised International Prognostic Scoring
• JMML juvenile myelomonocytic leukemia
• mCR refers to marrow complete remission
• MDS myelodysplastic syndromes
• MPN myeloproliferative neoplasm
• OS refers to overall survival.
• PR refers to partial remission
• RAEB refractory anemia with excess blasts.
• sAML secondary acute myeloid leukemia
• SE1 refers to Safety Expansion Cohort 1.
• SE2 refers to Safety Expansion Cohort 2.
• TEAE treatment-emergent adverse events
• tMDS refers to treatment-related or therapy-related myelodysplastic syndromes.
• a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 200 mg, 100 mg, 70 mg, or 50 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor.
• a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 200 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a moderate CYP3 A inhibitor.
• the moderate CYP3 A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 200 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a moderate CYP3 A inhibitor; wherein the moderate CYP3 A 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 wherein the venetoclax is administered
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 200 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a moderate CYP3 A inhibitor; wherein the moderate CYP3 A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, fluvoxamine, imatinib, tofisopam, and verapamil; wherein the venetoclax is administered on a prepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, dil
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a strong CYP3 A inhibitor.
• the strong CYP3 A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir combinations, elvitegravir/ritonavir combinations, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir combinations, nefazodone, nelfmavir, paritaprevir/ritonavir combinations, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir combinations, troleandomycin, and voriconazole.
• the daily dose of venetoclax is 100 mg. In some aspects, the daily dose of venetoclax is 50 mg.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a strong CYP3 A inhibitor; wherein the strong CYP3 A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir combinations, elvitegravir/ritonavir combinations, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir combinations, nefazodone, nelfmavir, parita
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a strong CYP3 A inhibitor; wherein the strong CYP3 A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir combinations, elvitegravir/ritonavir combinations, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir combinations, nefazodone, nelfmavir, parita
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 50 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a strong CYP3 A inhibitor; wherein the strong CYP3 A inhibitor is selected from the group consisting of boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir combinations, elvitegravir/ritonavir combinations, idelalisib, indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir combinations, nefazodone, nelfmavir, parita
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 70 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole.
• a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 70 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole; and wherein the venetoclax is administered on each of days 1-14 of the dosing cycle.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 70 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole; wherein the venetoclax is administered on each of days 1-14 of the dosing cycle; and wherein the 7 days the daily dose of azacitidine is during a first 9 days of the 28 day dosing cycle.
• the azacitidine is administered intravenously. In some 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 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole.
• a method for treating myelodysplastic syndromes in a human subject comprising administering to the human subject a daily dose of 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole; and wherein the venetoclax is administered on each of days 1-14 of the dosing cycle.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of 100 mg of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and posaconazole; wherein the venetoclax is administered on each of days 1-14 of the dosing cycle; and wherein the 7 days the daily dose of azacitidine is during a first 9 days of the 28 day dosing cycle.
• the azacitidine is administered intravenously.
• 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 venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, 100 mg when administered in combination with a strong CYP3 A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole.
• 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 venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, 100 mg when administered in combination with a strong CYP3 A inhibitor other than posaconazole, and 70 mg when administered in combination with posaconazole; wherein the moderate CYP3 A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, d
• the venetoclax is administered on each of days 1-14 of the dosing cycle. In other aspects, the 7 days the daily dose of azacitidine is during a first 9 days of the 28 day dosing cycle. In some aspects, the azacitidine is administered intravenously. In some 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 venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 50 mg, or 70 mg, or 100 mg when administered in combination with a strong CYP3 A inhibitor.
• 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 venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 50 mg when administered in combination with a strong CYP3 A inhibitor.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 50 mg when administered in combination with a strong CYP3 A inhibitor; wherein the moderate CYP3 A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole
• the venetoclax is administered on each of days 1-14 of the dosing cycle. In other aspects, the 7 days the daily dose of azacitidine is during a first 9 days of the 28 day dosing cycle. In some aspects, the azacitidine is administered intravenously. In some 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 venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 100 mg when administered in combination with a strong CYP3 A inhibitor.
• a method for treating myelodysplastic syndromes in a human subject comprises administering to the human subject a daily dose of venetoclax for 14 days in a 28 day dosing cycle, a daily dose of 75 mg/m 2 of azacitidine for 7 days in a 28 day dosing cycle, and a CYP3 A inhibitor; wherein the daily dose of venetoclax is: 200 mg when administered in combination with a moderate CYP3 A inhibitor, and 70 mg, or 100 mg when administered in combination with a strong CYP3 A inhibitor; wherein the moderate CYP3 A inhibitor is selected from the group consisting of aprepitant, cimetidine, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin,
• the venetoclax is administered on each of days 1-14 of the dosing cycle. In other aspects, the 7 days the daily dose of azacitidine is during a first 9 days of the 28 day dosing cycle. In some aspects, the azacitidine is administered intravenously. In some 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.
• IMS International Prognostic Scoring System
• IVS-R Revised IPSS
• IPSS-R Revised International Prognostic Scoring System
• RAEB refractory anemia with excess blasts
• RAEB-2 refractory anemia with excess blasts
• the IPSS-R is now also considered a well-validated assessment tool to identify patients who are commonly considered clinically appropriate to receive active treatment.
• the Revised International Prognostic Scoring System (IPSS-R) is shown in Table 2 and includes a refined classification of cytogenetic abnormalities, more specific cut-offs for bone marrow blast counts and cytopenias, and is weighted for their severity.
• the Revised International Prognostic Scoring System risk groups for myelodysplastic syndromes are defined based an overall score.
• the overall score is calculated as the sum of the blast score, cytogenetics score, hemoglobin score, platelets score, and absolute neutrophil count score.
• Table 2 Revised International Prognostic Scoring System (IPSS-R) Criteria and Scoring for
• 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.
• a treatment dose reduction may be indicated.
• Stepwise azacitidine dose modification occurred followed by adjustment of the venetoclax treatment from 14 to 7 days at the last step after all azacitidine dose modification steps have occurred. Venetoclax and azacitidine were resumed on the same day after any delays or interruptions in treatment.
• Table 8 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.
• FIGs. 1 and 2 The mean value of absolute neutrophil count and platelet count is shown in FIGs. 1 and 2, respectively.
• the number of count observations per study cycle day for both absolute neutrophil count and platelet count is shown in Table 11.
• Venetoclax dose modifications in patients receiving moderate or strong CYP3 A inhibitors were used in subsequent clinical studies as shown in Table 12 and Table 13.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Dermatology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=84028802

Family Applications (1)

Country Status (11)

Cited By (1)

Families Citing this family (1)

Citations (3)

• 2022
  • 2022-05-10 WO PCT/US2022/028434 patent/WO2022240788A1/en not_active Ceased
  • 2022-05-10 CN CN202280049025.3A patent/CN117651556A/zh not_active Withdrawn
  • 2022-05-10 IL IL308318A patent/IL308318A/en unknown
  • 2022-05-10 AU AU2022273615A patent/AU2022273615A1/en not_active Abandoned
  • 2022-05-10 BR BR112023023638A patent/BR112023023638A2/pt unknown
  • 2022-05-10 EP EP22808147.7A patent/EP4337208A4/en not_active Withdrawn
  • 2022-05-10 CA CA3219761A patent/CA3219761A1/en active Pending
  • 2022-05-10 MX MX2023013361A patent/MX2023013361A/es unknown
  • 2022-05-10 KR KR1020237042683A patent/KR20240006660A/ko active Pending
  • 2022-05-10 JP JP2023569873A patent/JP2024517935A/ja active Pending
  • 2022-05-10 US US17/741,356 patent/US20220370481A1/en not_active Abandoned

Patent Citations (3)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events