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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 ECHO or MUGA, collection of blood and CSF samples, lumbar puncture, and bone marrow aspiration throughout the trial.

Undergo collection of blood and CSF samples

Biospecimen Collection

Bone Marrow Aspiration

Calaspargase Pegol

Echocardiography

Fludarabine Phosphate

Hydrocortisone Sodium Succinate

Lumbar Puncture

Multigated Acquisition Scan

Revumenib

Vincristine Sulfate

Site Public Contact

Matthew A. Kutny

Aarati V. Rao

Emad K. Salman

Iftikhar Hanif

Maggie E. Fader

Gabrielle Lapping-Carr

Amanda Saraf

David S. Dickens

Joshua W. Goldman

Kathleen J. Yost

Peter M. Gordon

Kevin F. Ginn

Jeffrey A. Magee

Robin D. Hanson

Jing Chen

Teena Bhatla

Lauren R. Weintraub

Philip M. Monteleone

Thomas B. Alexander

Erin Wright

Erin H. Breese

Mukund G. Dole

Bill H. Chang

Kathrin M. Bernt

Jenny Ruiz

Stuart L. Cramer

Matthew Rees

Stanton C. Goldman

Caroline Smith

Joanna S. Yi

Timothy C. Griffin

Eric J. Lowe

Kelly E Faulk

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.

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.

A Study of SNDX-5613 in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia

A Phase 2 Study of SNDX-5613 in Combination With Chemotherapy for Patients With Relapsed or Refractory KMT2A-Rearranged Infant Leukemia

Ribonucleic acid (RNA) will be isolated from cryopreserved leukemic cell suspensions and exploratory analysis of RNA sequencing (Seq) will be performed. Principal component analysis and gene set enrichments will be used to compare overall transcriptional signatures, and specifically the reported KMT2A-R dependent gene sets, comparing paired pre-treatment and post-treatment samples. Correlations between changes in RNA-Seq and patient's clinical response to SNDX-5613 as well as pharmacokinetic parameters and menin displacement will be described.

Pre-treatment and post-treatment paired samples will be tested for menin occupancy by CUT\&RUN, and changes to informative histone modifications/protein complexes evaluated by CUT\&Tag. The degree of reduction in menin binding to specific target genes will be correlated with clinical response and pharmacokinetic parameters, as well as biologic transcriptional changes.

MRD negative remission rates will be summarized.

Analyses will be conducted for lymphoid and myeloid blocks separately and then combined and will be restricted to patients who receive calaspargase-pegol-mknl. These analyses will be exploratory and descriptive.

The types of anti-cancer therapies received by patients before or after administration of SNDX-5613 will be described. The association between the anti-cancer therapies patients received prior to enrollment and response may also be assessed. The association between the anti-cancer therapies received after SNDX-5613 and EFS or OS may be assessed. These analyses will be exploratory and descriptive.

Regimen A Cycle 1 will be used for determination of recommended phase 2 dose (RP2D)-lymphoid (L) directed chemotherapy block. A patient will be considered as being evaluable for DLT if: (1) the patient receives at least 66 doses of the first planned 28 days (84 doses) of SNDX- 5613 for the cycle (for patients with delayed SNDX-5613 shipment, will count 28 days from the start of SNDX-5613); or (2) the patient experiences a DLT after the start of SNDX-5613 in Cycle 1.

Regimen B Cycle 1 and Regimen A Cycle 2 will be used for determination of RP2D-myeloid (M) directed chemotherapy block. For each cycle mentioned above, a patient will be considered as being evaluable for DLT if: (1) the patient receives at least 66 doses of the first planned 28 days (84 doses) of SNDX- 5613 for the cycle (for patients with delayed SNDX-5613 shipment, will count 28 days from the start of SNDX-5613); or (2) the patient experiences a DLT after the start of SNDX-5613 in that cycle. For determination of RP2D-M, patients in Regimen A who have experienced a DLT in Cycle 1 or who have been evaluated as having Early Progressive Disease in Cycle 1 are excluded.

A patient with R/R infant KMT2A-R ALL will be included in the primary analysis of MRD negative remission rate if the patient is enrolled at RP2D-L and RP2D-M (in the safety phase or the expansion phase) and receives at least one dose of protocol treatment. This response rate will be estimated using the approach of Jung and Kim. The corresponding 95% confidence interval will be calculated using the approach of Koyama and Chen.

Analyses will be conducted for lymphoid and myeloid blocks separately and then combined. Will monitor if there is evidence that the proportion of patients achieving desired PK is considerably lower than 90% using the Pocock stopping boundaries.

Will be estimated using the Kaplan-Meier method.

Grade 3+ adverse events (AEs) will be summarized among patients receiving monotherapy, by cycles, and the proportion of patients having grade 3+ AEs will be estimated.

Children's Oncology Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of SNDX-5613 in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia	NCT05761171	Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Mixed... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Mixe...	Biospecimen Col... Bone Marrow Asp... Calaspargase Pe... Cytarabine Echocardiograph... Fludarabine Pho... Hydrocortisone ... Lumbar Puncture Methotrexate Multigated Acqu... Prednisolone Prednisone Revumenib Vincristine Sul...	1 Month - 6 Years	Children's Oncology Group
A Study of SNDX-5613 in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia	NCT05761171	Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Acute... Recurrent Mixed... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Acut... Refractory Mixe...	Biospecimen Col... Bone Marrow Asp... Calaspargase Pe... Cytarabine Echocardiograph... Fludarabine Pho... Hydrocortisone ... Lumbar Puncture Methotrexate Multigated Acqu... Prednisolone Prednisone Revumenib Vincristine Sul...	1 Month - 6 Years	Children's Oncology Group

Spots Global Cancer Trial Database for refractory acute myeloid leukemia due to lineage switch from acute leukemia of ambiguous lineage