A Phase 2 Study Evaluating Olutasidenib in Combination with Hypomethylating Agents in Patients with IDH1-mutated Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Advanced Myeloproliferative Neoplasm

Eligibility Criteria

• 1. Pathologically proven higher-risk MDS/CMML or advanced MPN
• 1. MDS/CMML participants must have International Prognostic Scoring System (IPSS) intermediate-2- or high-risk disease or Revised IPSS (IPSS-R) score \> 3.5 or Molecular IPSS (IPSS-M) moderate high-, high-, or very high-risk disease or bone marrow blast percentage.
• 2. Advanced MPN is defined as bone marrow blast percentage \>/=10%.
• 3. Participants on the treatment-naive arm must not have received a prior HMA. Agents such as growth factors (e.g. erythropoietin stimulating agents, luspatercept, eltrombopag, granulocyte colony stimulating factors), cyclosporine, and/or hydroxyurea are allowed.
• 2. Participants must have a documented IDH1 mutation
• 3. Participants \>/= 18 years old
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix A)
• 5. Acceptable liver function
• 1. Bilirubin \</= 2 times upper limit of normal (ULN) or \</= 3 times ULN in participants with Gilbert Syndrome
• 2. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase \</= 3 times ULN
• 6. Acceptable renal function with serum creatinine \</= 1.5 times ULN or calculated creatinine clearance \>/= 50 mL/min (as assessed by Cockcroft-Gault, MDRD, or CKD-Epi validated measures)
• 7. Negative serum or urine pregnancy test if female of childbearing potential
• 8. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication
• 9. Agreement for male participants not to donate sperm and for female participants of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug
• 10. Ability and willingness to sign informed consent prior to beginning study and undergoing procedures
• 1. Participants unable to swallow oral medications, or participants with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
• 2. Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening severe infection or psychiatric illness, which could place the participant at unacceptable risk of study treatment
• 3. Known active hepatitis B (HBV) or hepatitis C (HCV) or HIV infection
• 4. Pregnant or nursing women or women of childbearing potential not using highly effective contraception; male participants not using highly effective contraception
• 5. Participants with white blood cell count \> 25 x109/L Note: hydroxyurea use is permitted to meet this criterion
• 6. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care