A Study of Revumenib 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

This phase II trial tests the safety and best dose of 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia; Recurrent Mixed Phenotype Acute Leukemia; Refractory Mixed Phenotype Acute Leukemia; Refractory Acute Leukemia of Ambiguous Lineage; Recurrent Acute Leukemia of Ambiguous Lineage; Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage; Recurrent Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged; Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia; Refractory Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage; Refractory Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged; Refractory Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia
• Intervention / Treatment: Procedure: Lumbar Puncture; Drug: Methotrexate; Drug: Vincristine Sulfate; Drug: Cytarabine; Drug: Fludarabine Phosphate; Drug: Hydrocortisone Sodium Succinate; Procedure: Bone Marrow Aspiration; Procedure: Multigated Acquisition Scan; Drug: Prednisolone; Drug: Prednisone; Drug: Revumenib; Drug: Calaspargase Pegol; Procedure: Electrocardiogram; Procedure: Biospecimen Collection; Procedure: Echocardiography Test

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1V 4G2
    • CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Kaiser Permanente Downey Medical Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33908
      • Golisano Children's Hospital of Southwest Florida
    • Gainesville, Florida, United States, 32610
      • UF Health Cancer Institute - Gainesville
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital/Joe DiMaggio Children's Hospital
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
    • Tampa, Florida, United States, 33607
      • Saint Joseph's Hospital/Children's Hospital-Tampa
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Arthur M Blank Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Alliance for Childhood Diseases/Cure 4 the Kids Foundation
    • Reno, Nevada, United States, 89502
      • Renown Regional Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134
      • Saint Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Prisma Health Richland Hospital
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • San Antonio, Texas, United States, 78207
      • Children's Hospital of San Antonio
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.
• 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. Patients who have experienced lineage switch to acute myeloid leukemia (AML) are eligible assuming documented prior diagnosis of KMT2A-rearranged ALL/ALAL/MPAL. 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.

• Disease status at time of enrollment must be one of the following:

  • First relapse (untreated): Any recurrence of marrow disease, with or without other extramedullary sites(s), at any point after achieving remission ("remission-1", per definition below) and meeting one of the below criteria. Patients must not have received any disease-directed therapy for the marrow relapse prior to enrollment, other than permitted cytoreduction.

    • 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)
  • Primary refractory, or failure to achieve remission-1: remission-1 is defined as < 1% marrow blasts by flow MRD and resolution of extramedullary disease following at least 2 courses of frontline chemotherapy. Patients who receive 2 courses of chemotherapy and 1 course of blinatumomab are also eligible, but no further treatment attempts beyond that are permitted

• 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.
• 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.
• Patients >= 12 months of age must have a performance status by Lansky Scale of >= 50%.
• Patients must be able to take enteral medications. Acceptable routes of administration for revumenib (SNDX-5613) include: oral (PO), nasogastric (NG) tube, nasojejunal (NJ) tube, nasoduodenal (ND), and gastrostomy tube (G-tube).

• 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 revumenib 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.

• A creatinine based on age as follows:

  • Age 1 month to < 6 months: maximum creatinine 0.4 mg/dL
  • Age 6 months to < 1 year: maximum creatinine 0.5 mg/dL
  • Age 1 to < 2 years: maximum creatinine 0.6 mg/dL

  • Age 2 to < 6 years: maximum 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 creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
• A direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, unless disease related

• 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
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram.
• Corrected QT interval using Fridericia formula (QTcF) of < 450 msec (using the average of triplicate measurements)
• 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 revumenib (SNDX-5613) on protocol therapy.
• Patients must be able to comply with the safety monitoring requirements of the study, in the opinion of the treating investigator.

Exclusion Criteria:

• Patients with isolated extramedullary leukemia.
• Patients diagnosed with Down syndrome.

• Patients known to have one of the following syndromes:

  • Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome.
• Patients with a secondary KMT2A-R leukemia that developed after treatment of prior malignancy with cytotoxic chemotherapy.
• Patients with a history of congenital prolonged QT syndrome, congestive heart failure or uncontrolled arrhythmia in the past 6 months prior to study enrollment.

• Patients with an active, uncontrolled infection, further defined below:

  • Positive bacterial blood culture within 48 hours of study enrollment
  • Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
  • A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
  • Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved. For patients with Clostridium (C.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
  • Active viral or protozoal infection requiring IV treatment
  • Human immunodeficiency virus (HIV)-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of enrollment.
• Patients with active acute graft-versus-host disease (GVHD) > grade 0 (unless skin only), or chronic GVHD > mild (unless skin only) are not eligible. Patients with acute or chronic skin GVHD that is =< grade 1, or chronic skin GVHD that is graded as mild are eligible.
• Patients who have received a prior solid organ transplantation.
• Patients with known Charcot-Marie-Tooth disease, if treating on Regimen A (with vincristine).
• CYP3A4 Inhibitors or Inducers: Strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers are prohibited during treatment, with the exception of strong CYP3A4 inhibitor -azoles during monotherapy cycles. These agents should be discontinued at least 5 half-lives prior to starting protocol therapy. Concomitant use of a strong CYP3A4 inhibitor -azole antifungal is permitted during the revumenib (SNDX-5613) monotherapy cycles, with appropriate revumenib (SNDX-5613) dose modification.
• P-glycoprotein (P-gp) inhibitors or inducers: Vincristine is a substrate for P-gp. Concomitant use of P-gp inhibitors or inducers with vincristine (patients receiving Regimen A Cycle 1) should be avoided.
• Investigational drugs: Patients who are currently receiving another investigational drug.
• Anti-cancer agents: Patients who are currently receiving other anti-cancer agents (exceptions: hydroxyurea and corticosteroids, which may be used as cytoreduction prior to enrollment).
• Anti-GVHD agents: Patients who are receiving cyclosporine, tacrolimus, or other systemic agents to treat graft-versus-host disease post bone marrow transplant. Patients should discontinue anti-GVHD agents > 7 days prior to enrollment and have no evidence of worsening GVHD. Topical steroids are permitted.
• Patients who have previously been treated with revumenib (SNDX-5613). Prior exposure to other menin inhibitors is permitted.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen A (revumenib, 3-drug re-induction, FLA); See Detailed Description.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Drug: Methotrexate; Given IT; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Vincristine Sulfate; Given IV; Other Names: Oncovin; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Vincasar; Vincosid; Vincrex; Vincristine, sulfate; Drug: Cytarabine; Given IV and IT; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Hydrocortisone Sodium Succinate; Given IT; Other Names: (11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt; A-Hydrocort; Buccalsone; Corlan; Cortisol Sodium Succinate; Cortop; Efcortelan; Emergent-EZ; Flebocortid; Hidroc Clora; Hycorace; Hydro-Adreson; Hydrocort; Hydrocortisone 21-Sodium Succinate; Hydrocortisone Na Succinate; Kinogen; Nordicort; Nositrol; Sinsurrene; Sodium hydrocortisone succinate; Solu-Cortef; Solu-Glyc; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Multigated Acquisition Scan; Undergo MUGA scan; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Drug: Prednisolone; Given PO or via NG, NJ, ND or G-tube; Other Names: (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione; .delta.1-Hydrocortisone; Adnisolone; Aprednislon; Capsoid; Cortalone; Cortisolone; Dacortin H; Decaprednil; Decortin H; Delta(1)Hydrocortisone; Delta- Cortef; Delta-Cortef; Delta-Diona; Delta-F; Delta-Phoricol; Delta1-dehydro-hydrocortisone; Deltacortril; Deltahydrocortisone; Deltasolone; Deltidrosol; Dhasolone; Di-Adreson-F; Dontisolon D; Estilsona; Fisopred; Frisolona; Gupisone; Hostacortin H; Hydeltra; Hydeltrasol; Klismacort; Kuhlprednon; Lenisolone; Lepi-Cortinolo; Linola-H N; Linola-H-Fett N; Longiprednil; Metacortandralone; Meti Derm; Meticortelone; Opredsone; Panafcortelone; Precortisyl; Pred-Clysma; Predeltilone; Predni-Coelin; Predni-Helvacort; Prednicortelone; Prednisolonum; Prelone; Prenilone; Sterane; Drug: Prednisone; Given PO or via NG, NJ, ND or G-tube; Other Names: Deltasone; Orasone; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; Drug: Revumenib; Given PO or via NG, NJ, ND or G-tube; Other Names: Menin-Mixed Lineage Leukemia Protein-Protein Interaction Inhibitor SNDX-5613; Menin-MLL Inhibitor SNDX-5613; Menin-MLL Interaction Inhibitor SNDX-5613; SNDX 5613; SNDX-5613; SNDX5613; Drug: Calaspargase Pegol; Given IV; Other Names: Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl); Asparlas; EZN-2285; SC-PEG E. Coli L-Asparaginase; Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase; Calaspargase Pegol-mknl; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Procedure: Biospecimen Collection; Undergo collection of blood and CSF samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC
Experimental: Regimen B (revumenib, FLA); 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 ECHO or MUGA, ECG, collection of blood, CSF and bone marrow samples, lumbar puncture, and bone marrow aspiration throughout the trial.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Drug: Methotrexate; Given IT; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Cytarabine; Given IV and IT; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Hydrocortisone Sodium Succinate; Given IT; Other Names: (11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt; A-Hydrocort; Buccalsone; Corlan; Cortisol Sodium Succinate; Cortop; Efcortelan; Emergent-EZ; Flebocortid; Hidroc Clora; Hycorace; Hydro-Adreson; Hydrocort; Hydrocortisone 21-Sodium Succinate; Hydrocortisone Na Succinate; Kinogen; Nordicort; Nositrol; Sinsurrene; Sodium hydrocortisone succinate; Solu-Cortef; Solu-Glyc; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Multigated Acquisition Scan; Undergo MUGA scan; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Drug: Revumenib; Given PO or via NG, NJ, ND or G-tube; Other Names: Menin-Mixed Lineage Leukemia Protein-Protein Interaction Inhibitor SNDX-5613; Menin-MLL Inhibitor SNDX-5613; Menin-MLL Interaction Inhibitor SNDX-5613; SNDX 5613; SNDX-5613; SNDX5613; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Procedure: Biospecimen Collection; Undergo collection of blood and CSF samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicities (DLTs) for lymphoid directed chemotherapy block (Safety Phase)	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 44 doses of the first planned 28 days (56 doses) of revumenib for cycle 1 (for patients with delayed revumenib shipment, will count 28 days from the start of revumenib); or (2) the patient experiences a DLT after the start of revumenib in that cycle.	At the end of Cycle 1 of Regimen A (each cycle is a minimum of 29 days)
Minimal residual disease (MRD) negative remission rate in patients with relapsed/refractory (R/R) infant KMT2A-R ALL among patients >= 6 months at enrollment (Expansion Phase)	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.	Up to 3 cycles of combination therapy (each cycle is a minimum of 29 days)
Incidence of dose-limiting toxicities (DLTs) for myeloid directed chemotherapy block (Safety Phase)	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 44 doses of the first planned 28 days (56 doses) of revumenib for the cycle (for patients with delayed revumenib shipment, will count 28 days from the start of revumenib); or (2) the patient experiences a DLT after the start of revumenib 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.	At the end of Cycle 1 of Regimen B and at the end of Cycle 2 of Regimen A (each cycle is a minimum of 29 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimation of 18-month overall survival (OS) rate in patients with R/R infant KMT2A-R ALL	Will be estimated using the Kaplan-Meier method.	Time from date of enrollment to death due to any cause, assessed up to 18 months
Characterization of tolerability of revumenib given as monotherapy in patients with R/R infant KMT2A-R ALL	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.	Up to 2 years from enrollment
Proportion of patients achieving desired SNDX-5613 pharmacokinetics (PK)	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.	Up to 2 years from enrollment
Estimation of 18-month event-free survival (EFS) rate in patients with R/R infant KMT2A-R ALL	Will be estimated using the Kaplan-Meier method. Cumulative incidence rates of each EFS event type (relapse, SMN and death) will be estimated and be presented with cumulative incidence curves.	Time from date of enrollment to date of treatment failure, relapse, second or secondary malignancy (SMN), or death due to any cause, whichever occurs first, assessed up to 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in KMT2A-R transcriptional program	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.	Up to 5 years from enrollment
Changes to menin displacement	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.	Up to 5 years from enrollment
MRD negative remission rates in patients with R/R non-infant KMT2A-R ALL	MRD negative remission rates will be summarized.	Up to 3 cycles of combination therapy (each cycle is a minimum of 29 days)
Anti-cancer therapies received before and after administration of revumenib by patients with R/R KMT2A-R ALL	The types of anti-cancer therapies received by patients before or after administration of revumenib 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 revumenib and EFS or OS may be assessed. These analyses will be exploratory and descriptive.	Up to 5 years from enrollment
PK of calaspargase pegol and the associated toxicities for patients with R/R KMT2A-R ALL	Analyses will be conducted for lymphoid and myeloid blocks separately and then combined and will be restricted to patients who receive calaspargase-pegol. These analyses will be exploratory and descriptive.	Up to 5 years from enrollment
MRD negative remission rate in patients with R/R infant KMT2A-R ALL among patients < 6 months at enrollment	The overall MRD negative remission rate after treatment with revumenib in combination with chemotherapy will be described among patients < 6 months at enrollment. The MRD negative remission rate will be described by dose level.	Up to 3 cycles of combination therapy (each cycle is a minimum of 29 days)

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Investigators: Principal Investigator: Kelly E Faulk, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: March 8, 2023
• First Posted (Actual): March 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Biopsy; Alkaloids; Polycyclic Compounds; Hydrolases; Enzymes; Enzymes and Coenzymes; Indoles; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Nucleosides; Pterins; Pteridines; Pregnadienetriols; Pregnadienediols; Amidohydrolases; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Diagnostic Techniques, Neurological; Methotrexate; Prednisone; Prednisolone; Cytarabine; Vincristine; Methylprednisolone; Hydrocortisone; Asparaginase; Specimen Handling; fludarabine phosphate; Spinal Puncture; deltacortene; prednylidene; calaspargase pegol; merphos; revumenib; hydrocortisone hemisuccinate
• Other Study ID Numbers: AALL2121 (Other Identifier: CTEP); U10CA180886 (U.S. NIH Grant/Contract); NCI-2023-00503 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes