DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

This phase I/II trial studies the effect of DS-1594b with or without azacitidine, venetoclax, or mini-HCVD in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has come back (recurrent) or not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, venetoclax, and mini-HCVD, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. DS-1594b may inhibit specific protein bindings that cause blood cancer. Giving DS-1594b, azacitidine, and venetoclax, or mini-HCVD may work better in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia.

OUTLINE: This is a phase I, dose-escalation study of DS-1594b followed by a phase II study. PHASE I: Patients receive DS-1594b orally (PO) twice daily (BID) on days 1-28 in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are assigned to 1 of 4 cohorts. COHORT A: Patients with MLLr receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. COHORT B: Patients with NPM1m receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. COHORT C: Patients receive DS-1594b PO BID on days 1-28, venetoclax PO QD on days 1-28, and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. COHORT D: Patients receive DS-1594b PO BID on days 1-28. For cycles 1, 3, 5, 7, patients also receive cyclophosphamide IV over 3 hours on days 1-3, mesna IV over 24 hours on days 1-3, vincristine IV on days 1 and 11, dexamethasone PO or IV on days 1-4 and 11-14, filgrastim SC on days 1-28, methotrexate intrathecally (IT) on day 2 of cycles 1 and 3, and cytarabine IT on day 7 of cycles 1 and 3. For cycles 2, 4, 6, 8, patients also receive methotrexate IV over 24 hours on day 1, cytarabine BID IV over 3 hours on days 2 and 3, leucovorin IV or PO every 6 hours (Q6H) starting 12 hours after completion of methotrexate, filgrastim SC days 1-28, cytarabine IT on day 5-8 of cycles 2 and 4 and methotrexate IT on days 8-11 of cycles 2 and 4. Patients with CD20 expression may also receive rituximab IV on days 1 and 11 of cycles 1 and 3 and days 1 and 8 of cycles 2 and 4. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive DS-1594b PO BID on days 1-28, vincristine IV over 15 minutes on day 7 and prednisone PO BID on days 1-5. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at days 30 and 100.