A Study of Revumenib in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia

PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of revumenib administered in combination with chemotherapy in patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2A-R) acute lymphoblastic leukemia (ALL). II. To estimate the minimal residual disease (MRD) negative remission rate of patients age \>= 6 months at enrollment with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics (PK) of revumenib administered with chemotherapy in patients with R/R infant KMT2A-R ALL. II. To estimate the 18-month event-free survival (EFS) of patients with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. III. To estimate 18-month overall survival (OS) of patients with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. IV. To characterize the tolerability of revumenib given as monotherapy in patients with R/R infant KMT2A-R ALL. EXPLORATORY OBJECTIVES: I. To assess the biologic activity of revumenib administered with chemotherapy in patients with R/R KMT2A-R ALL. II. To estimate the MRD negative remission rate of patients with R/R non-infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. III. To characterize the PK of calaspargase pegol and describe associated toxicities for patients with R/R KMT2A-R ALL. IV. To describe the anti-cancer therapies received before and after administration of revumenib by patients with R/R KMT2A-R ALL. V. To describe the MRD negative remission rate of patients age \< 6 months at enrollment with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. OUTLINE: Patients with acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL) are assigned to 1 of 2 regimens, by physician discretion. Patients with acute myeloid leukemia (AML) are assigned to Regimen B. REGIMEN A: COMBINATION CYCLE 1: Patients receive revumenib orally (PO) or via nasogastric (NG), nasojejunal (NJ), nasoduodenal (ND) or gastrostomy tube (G-tube) every 12 hours continuously. Patients also receive "3-drug re-induction" consisting of vincristine intravenously (IV) on days 1, 8, 15, and 22, prednisone or prednisolone PO or via NG, ND, NJ, or G-tube twice daily (BID) on days 1-28, calaspargase pegol IV on day 4, as well as methotrexate (MTX) intrathecally (IT) on days 1 and 8 then optionally weekly, hydrocortisone IT, and cytarabine IT. Patients who have early progressive disease may continue to Combination Cycle 2 early before fully completing cycle 1. COMBINATION CYCLE 2: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously, "FLA" consisting of fludarabine IV and high-dose cytarabine IV on days 1-5, and MTX IT, hydrocortisone IT, and cytarabine IT on day 0 then optionally on days 8, 15, and 22. After completion of Combination Cycle 2, patients who experienced early progressive disease in Combination Cycle 1 continue to Combination Cycle 3. All other patients proceed to Monotherapy. COMBINATION CYCLE 3: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously, "FLA" as in Combination Cycle 2, MTX IT, hydrocortisone IT, and cytarabine IT on day 0. MONOTHERAPY: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT. REGIMEN B: COMBINATION CYCLES 1-2: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously, "FLA" consisting of fludarabine IV and high-dose cytarabine IV on days 1-5, and MTX IT, hydrocortisone IT, and cytarabine IT on day 0 then optionally on days 8, 15, and 22. Cycles are a minimum of 29 days in duration. MONOTHERAPY: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT. All patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), electrocardiogram (ECG), collection of blood, cerebrospinal fluid (CSF) and bone marrow samples, lumbar puncture, and bone marrow aspiration throughout the trial.