Decitabine and Venetoclax in Combination with Olutasidenib for the Treatment of Patients with Newly Diagnosed, Recurrent or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Age ≥ 18 years
• Subjects must have a documented IDH1 gene mutation
• Patients with a diagnosis of relapsed or refractory AML (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML), high-risk MDS (defined as > 5% blasts); OR
• Patients with newly diagnosed AML not eligible or appropriate for intensive chemotherapy are also eligible.(Phase 2 portion only)
• To be considered not eligible for intensive chemotherapy, participants must be defined by the following: Age 75 years or older, or age 18 to 74 years with at least one of the following comorbidities: * Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina). * Severe pulmonary disorder (eg, diffusing capacity of the lungs for carbon monoxide [DLCO] ≤ 65% or forced expiratory volume in 1 second [FEV1] ≤ 65%). * Creatinine clearance ≥ 30 mL/min to < 45 mL/min. * Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 x upper limit of normal (ULN) * Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3 * Any other comorbidity that per the investigator renders a patient inappropriate for intensive chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status </=2 (unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy)
• Adequate renal function including creatinine < 1.5, unless related to the disease or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy
• Adequate hepatic function (direct bilirubin < 2 x upper limit of normal [ULN] unless increase is due to Gilbert’s disease or leukemic involvement, and aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] < 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5 x ULN will be considered eligible, or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy)
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent intrathecal therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
• Male subjects who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 90 days after last dose of study drug.
• Willing and able to provide informed consent.

Exclusion Criteria

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML).
• Patients with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.
• Patients with active, uncontrolled leukemia involvement of the CNS
• Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant including active chronic graft-versus-host-disease (cGVHD) requiring topical therapy. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to the start of study treatment.
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
• Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known HIV infection.
• Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea and cytarabine is permitted to meet this criterion.)
• Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception. * Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide).