PRIMARY OBJECTIVES:~I. To determine the recommended phase 2 dose (RP2D) of revumenib (SNDX-5613) 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 with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy.~SECONDARY OBJECTIVES:~I. To characterize the pharmacokinetics (PK) of SNDX-5613 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 SNDX-5613 in combination with chemotherapy.~III. To estimate 18-month overall survival (OS) of patients with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy.~IV. To characterize the tolerability of SNDX-5613 given as monotherapy in patients with R/R infant KMT2A-R ALL.~EXPLORATORY OBJECTIVE:~I. To assess the biologic activity of SNDX-5613 administered with chemotherapy in patients with R/R KMT2A-R ALL.~OUTLINE: Patients with ALL, ALAL or MPAL are assigned to 1 of 2 regimens. Patients with 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). Patients also receive 3-drug re-induction consisting of vincristine intravenously (IV), prednisone or prednisolone PO or via NG, ND, NJ, or G-tube, pegaspargase or calaspargase pegol-mknl IV, as well as methotrexate (MTX) intrathecally (IT), 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, FLA consisting of fludarabine IV and high-dose cytarabine IV. 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, FLA as in Combination Cycle 2, MTX IT, hydrocortisone IT, and cytarabine IT.~MONOTHERAPY: Patients receive revumenib PO for up to 12 cycles on study. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated.~REGIMEN B:~COMBINATION CYCLES 1-2: Patients receive revumenib PO, NG, ND, NJ, or G-tube, FLA, MTX IT, hydrocortisone IT, and cytarabine IT for 2 cycles on study.~MONOTHERAPY: Patients receive revumenib PO for up to 12 cycles on study. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated.~All patients also undergo echocardiogram (ECHO) or multi-gated acquisition (MUGA) scans and collection of blood on study, and bone marrow collection throughout the trial.
This phase II trial tests the safety and best dose of revumenib when given together with chemotherapy, and how well the treatment regimen works for infants and young children with leukemia that has come back (relapsed) or does not respond to treatment (refractory) and is associated with a KMT2A (MLL) gene rearrangement (KMT2A-R). Revumenib is an oral medicine that directly targets the changes that occur in a cell with a KMT2A rearrangement and has been shown to specifically kill these leukemia cells in test tubes and animals. Drugs used in chemotherapy, such as vincristine, prednisone, asparaginase, fludarabine and cytarabine 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. This trial is being done to find out if the combination of revumenib and chemotherapy may help to treat the cancer cells better than either treatment alone.