Summary

This phase II trial tests the safety and best dose of SNDX-5613 (revumenib) in combination with chemotherapy, and evaluates whether this treatment improves the outcome in infants and young children who have leukemia that has come back (relapsed) or does not respond to treatment (refractory) and is associated with a KMT2A (MLL) gene rearrangement (KMT2A-R). Leukemia is a cancer of the white blood cells, where too many underdeveloped (abnormal) white blood cells, called “blasts”, are found in the bone marrow, which is the soft, spongy center of the bones that produces the three major blood cells: white blood cells to fight infection; red blood cells that carry oxygen; and platelets that help blood clot and stop bleeding. The blasts crowd out the normal blood cells in the bone marrow and spread to the blood. They can also spread to the brain, spinal cord, and/or other organs of the body. The leukemia cells of some children have a genetic change in which a gene (KMT2A) is broken and combined with other genes that typically do not interact with one another; this is called “rearranged”. This genetic rearrangement alters how other genes are turned on or off in the cell, turning on genes that drive the development of leukemia. Patients with KMT2A rearrangement have higher risk for cancer coming back after treatment. 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 preclinical laboratory settings and in 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 would be safe and/or effective in treating infants and young children with relapsed or refractory KMT2A-R leukemia.

Objectives

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.
II. To estimate the MRD negative remission rate of patients with R/R non-infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy.
III. To characterize the PK of calaspargase pegol-mknl 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 SNDX-5613 by patients with R/R KMT2A-R ALL.

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-mknl IV over 1-2 hours 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 over 60 minutes and high-dose cytarabine IV over 1-3 hours on days 1-5. 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. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated.

REGIMEN B:
COMBINATION CYCLES 1-2: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously, "FLA" IV on days 1-5, MTX IT, hydrocortisone IT, and cytarabine IT on day 0 and optionally on days 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 2 cycles.

MONOTHERAPY: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously. Treatment repeats every 28 days for up to 12 cycles on study in the absence of disease progression or unacceptable toxicity. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT on days 0, 8, 15 and 22 as clinically indicated.

All patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), collection of blood and cerebrospinal fluid (CSF) samples, lumbar puncture, and bone marrow aspiration throughout the trial.

Eligibility

1. Patients must be 1 month to < 6 years old at the time of study enrollment and must have had initial diagnosis of leukemia at < 2 years old.
2. Patients must have KMT2A-rearranged acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL), which is determined to be refractory or in first marrow relapse. All patients must undergo cytogenetics and fluorescence in situ hybridization (FISH) testing of a relapsed/refractory blast sample at a Children's Oncology Group (COG)-approved laboratory for KMT2A-R status determination and the presence of a KMT2A- rearrangement must be confirmed by central review. Cytogenetics results must be submitted for central review by Day 10 of protocol therapy, for confirmation of KMT2A-R status. Patients enrolled with refractory disease may utilize initial diagnostic cytogenetics for eligibility and submission for central review if testing was performed at a COG approved laboratory. Patients will be eligible to remain on protocol therapy if KMT2A-R is confirmed by central review. Additional methods of assessing for KMT2A-R may be considered if FISH does not detect the rearrangement.
3. Disease status at time of enrollment must be one of the following: * First relapse: Any recurrence of marrow disease, with or without other extramedullary sites(s), at any point after achieving remission. (“Remission-1”, per definition below) meeting one of these criteria: ** Relapse M1: M1 morphology (< 5% blasts) + at least 2 confirmatory tests showing >= 1% blasts (testing includes flow, cytogenetics, polymerase chain reaction [PCR]/next-generation sequencing [NGS] of immunoglobulin [Ig]/T-cell receptor [TCR] rearrangement, and/or PCR or NGS of fusion gene identical to diagnosis), OR ** Relapse M2: M2 morphology (5-25% blasts) + 1 confirmatory test showing > 1% blasts, OR ** Relapse M3: M3 morphology (> 25% blasts) * Refractory, or failure to achieve Remission-1: Remission-1 is defined as < 1% marrow blasts by flow minimal residual disease (MRD) and resolution of extramedullary disease by the end of Consolidation, or 2 courses of frontline chemotherapy.
4. Central Nervous System (CNS) disease: Patients must have CNS1 or CNS2 status and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsy. * Patients with CNS3 disease may receive antecedent intrathecal chemotherapy to achieve CNS1 or CNS2 status prior to enrollment. * Patients with a history of CNS chloromatous disease are required to have no radiographic evidence of CNS disease prior to enrollment.
5. White blood cell (WBC) must be < 50,000/uL at the time of study enrollment. Patients can receive cytoreduction with hydroxyurea and/or corticosteroids for up to 7 days prior to enrollment.
6. Patients >= 12 months of age must have a performance status by Lansky Scale of >= 50%.
7. Patients must be able to take enteral medications. Acceptable routes of administration for SNDX-5613 include: oral (PO), nasogastric (NG) tube, nasojejunal (NJ) tube, nasoduodenal (ND), and gastrostomy tube (G-tube).
8. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: ** >= 14 days must have elapsed after the completion of other cytotoxic therapy, including patients who relapse during pre-Maintenance upfront therapy, with these specific exceptions: cytoreduction with hydroxyurea and/or corticosteroids, and intrathecal chemotherapy, which have no required washout periods. For patients who relapse during upfront Maintenance therapy, >= 7 days must have elapsed after the last dose of chemotherapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. *** NOTE: Cytoreduction with hydroxyurea and/or corticosteroids is permitted prior to enrollment for patients with WBC >= 50,000/uL, and by provider discretion regardless of WBC, to reduce potential risk of differentiation syndrome with SNDX-5613 initiation. Hydroxyurea and/or corticosteroids may be given for up to 7 days, with no wash-out required. *** NOTE: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy that is given up to 7 days prior to the initiation of protocol therapy counts as protocol therapy and not prior anti-cancer therapy. Intrathecal chemotherapy given > 7 days prior does not count as protocol therapy. *** NOTE: Prior exposure to fludarabine and cytarabine (FLA) is permitted. * Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. * Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria. * Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or >= 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator. * Interleukins, Interferons and Cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon, or cytokines * Stem cell infusions (with or without total body irradiation (TBI): ** Allogeneic (non-autologous) bone marrow or stem cell transplant, or stem cell boost: >= 84 days after infusion ** Donor leukocyte infusion: >= 28 days * Cellular Therapy: >= 28 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) * Radiation Therapy (XRT)/External Beam Irradiation including protons: >= 14 days after local XRT; >= 84 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow radiation.
9. A serum creatinine based on age as follows: * Age 1 month to < 6 months: maximum serum creatinine 0.4 mg/dL * Age 6 months to < 1 year: maximum serum creatinine 0.5 mg/dL * Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL * Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL OR **a 24-hour urine Creatinine clearance >= 70 mL/min/1.73 m^2 OR ** a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard). * NOTE: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
10. A direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, unless disease related
11. Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3 x ULN) unless disease related. * Note: For the purpose of eligibility, the ULN for SGPT (ALT) has been set to the value of 45 U/L
12. Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram.
13. Corrected QT interval using Fridericia formula (QTcF) of < 450 msec (using the average of triplicate measurements)
14. NOTE: There are no specific electrolyte parameters for eligibility. However, it should be noted that, to limit QTc prolongation risk, patients must maintain adequate potassium and magnesium levels to initiate and continue SNDX-5613 on protocol therapy.
15. Patients must be able to comply with the safety monitoring requirements of the study, in the opinion of the treating investigator.