A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

NCT04065399 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: SNDX-5613-07002020-004104-34
• Study Type: interventional
• Target: 447
• Locations: 11 countries
• Sites: 57

Brief Summary

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib in participants with acute leukemia. In Phase 2, participants will be enrolled in 4 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib.

Conditions

Acute Lymphoblastic Leukemia; Mixed Lineage Acute Leukemia; Mixed Phenotype Acute Leukemia; Acute Myeloid Leukemia; Acute Leukemia of Ambiguous Lineage

Keywords

AML; ALL; MPAL; MLAL; ALAL; relapsed leukemia; refractory leukemia; acute leukemia; KMT2A; NPM1

Outcome Measures

Primary Outcomes (9)

• Number of participants with dose-limiting toxicities (DLTs) (Phase 1)

  Assessed by the NCI CTCAE version 5.0 (Phase 1)

  Approximately 1 year

• Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)

  Assessed by the NCI CTCAE version 5.0 (Phase 1)

  Approximately 1 year

• Cmax (Phase 1)

  Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1)

  Approximately 1 year

• Tmax (Phase 1)

  Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1)

  Approximately 1 year

• AUC0-t (Phase 1)

  Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of revumenib and relevant metabolites (Phase 1)

  Approximately 1 year

• CR+CRh rate (Phase 2 [Cohorts 2A-2C])

  To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2 \[Cohorts 2A-2C\])

  Approximately 3 years

• Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C])

  Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohorts 2A-2C\])

  Approximately 3 years

• Cmax (Phase 2 [Cohort 2D])

  Cmax of revumenib (Phase 2 \[Cohort 2D\])

  Approximately 3 years

• AUC0-tau (Phase 2 [Cohort 2D])

  Area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) of revumenib (Phase 2 \[Cohort 2D\])

  Approximately 3 years

Secondary Outcomes (11)

• Transfusion independence (Phase 2 [Cohorts 2A-2C])

  Approximately 3 years

• CRc rate (Phase 2 [Cohorts 2A-2C])

  Approximately 3 years

• ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2 [Cohorts 2A-2C])

  Approximately 3 years

• TTR (Phase 2 [Cohorts 2A-2C])

  Approximately 34 months

• DOR (Phase 2 [Cohorts 2A-2C])

  Approximately 3 years

Study Arms (1)

Revumenib

EXPERIMENTAL

Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib. Participants will be enrolled in 1 of 6 dose-escalation arms: * Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole * Arm B: Participants receiving any strong CYP3A4 inhibitors for antifungal prophylaxis * Arm C: Participants receiving revumenib and cobicistat * Arm D: Participants receiving fluconazole for antifungal prophylaxis * Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers * Arm F: Participants receiving isavuconazole for antifungal prophylaxis Phase 2: Oral revumenib; 4 indication-specific expansion cohorts will be enrolled: * Cohort 2A: Participants with KMT2Ar ALL/MPAL * Cohort 2B: Participants with KMT2Ar AML * Cohort 2C: Participants with NPM1m AML * Cohort 2D: Participants with acute leukemia (including KMT2Ar, NPM1m, NUP98r and other acute leukemias expected to have HOX/MEIS upregulation)

Drug: revumenib; Drug: cobicistat

Interventions

revumenib DRUG

revumenib orally

Also known as: SNDX-5613

Revumenib

cobicistat DRUG

Phase 1 Arm C participants will receive 150 mg cobicistat daily.

Revumenib

Eligibility Criteria

• Age: 30 Days+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020), or acute leukemia harboring KMT2A rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.
• Phase 1:
• Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
• Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
• Arm C: Participants receiving revumenib in combination with cobicistat.
• Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).
• Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
• Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.
• Phase 2:
• Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the NCCN Guidelines® for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).
• Cohort 2A: Documented R/R ALL/MPAL with KMT2A rearrangement.
• Cohort 2B: Documented R/R AML with KMT2A rearrangement.
• Cohort 2C: Documented R/R AML with NPM1m.
• Cohort 2D: Documented R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (for example, KMT2Ar, NPM1m, and NUP98r), including participants who are MRD-positive by multiparametric flow cytometry or molecular methods only, and including participants with isolated extramedullary disease.
• White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria.

You may not qualify if:

• Participants meeting any of the following criteria are not eligible for study participation:
• Diagnosis of active acute promyelocytic leukemia.
• Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C only).
• Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic).
• Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Participants with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
• Hepatitis B or C.
• Pregnant or nursing women.
• Cardiac Disease:
• Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
• Corrected QT interval (QTc) \>450 milliseconds.
• Gastrointestinal Disease:
• any gastrointestinal issue of the upper GI tract that might affect oral drug absorption or ingestion (that is, gastric bypass and gastroparesis).
• Cirrhosis with a Child-Pugh score of B or C.
• Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD \>Grade 0 within 4 weeks of enrollment. All transplant participants must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Participants may be on physiological doses of steroids.
• Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for example, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the participant is not receiving any systemic therapy or radiation.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead

Study Sites (57)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

ACTIVE NOT RECRUITING

University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital

Los Angeles, California, 90033, United States

COMPLETED

Stanford Cancer Institute

Palo Alto, California, 94305, United States

ACTIVE NOT RECRUITING

University of Colorado

Aurora, Colorado, 80045, United States

RECRUITING

Florida Cancer Specialists and Research Institute

Sarasota, Florida, 34232, United States

ACTIVE NOT RECRUITING

Moffitt Cancer Center

Tampa, Florida, 33162, United States

COMPLETED

Emory Winship Cancer Institute

Atlanta, Georgia, 30322, United States

RECRUITING

Children's Healthcare of Atlanta

Atlanta, Georgia, 30329, United States

COMPLETED

The University of Chicago Medical Center

Chicago, Illinois, 60637, United States

RECRUITING

University of Iowa Hospital

Iowa City, Iowa, 52246, United States

RECRUITING

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

ACTIVE NOT RECRUITING

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

COMPLETED

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

ACTIVE NOT RECRUITING

Montefiore Medical Center

New York, New York, 10467, United States

RECRUITING

Duke University Medical Center

Durham, North Carolina, 27110, United States

RECRUITING

University of Cincinnati

Cincinnati, Ohio, 45267, United States

COMPLETED

Ohio State University

Columbus, Ohio, 43201, United States

RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

ACTIVE NOT RECRUITING

Huntsman Cancer Institute at the University of Utah

Salt Lake City, Utah, 84112, United States

COMPLETED

Peter MacCallum Cancer Centre (PMCC)

Melbourne, Victoria, 3000, Australia

ACTIVE NOT RECRUITING

Royal Melbourne Hospital (RMH)

Parkville, Victoria, 3050, Australia

ACTIVE NOT RECRUITING

Alfred Hospital

Melbourne, 3004, Australia

RECRUITING

Sir Charles Gairdner Hospital

Nedlands, 6009, Australia

RECRUITING

Royal North Shore Hospital

Saint Leonards, 2065, Australia

RECRUITING

University Health Network

Toronto, M5G 2M9, Canada

RECRUITING

The Hospital for Sick Children

Toronto, Canada

ACTIVE NOT RECRUITING

Hospital Saint-Louis - APHP

Paris, 75010, France

RECRUITING

Centre Hospitalier Universitaire (CHU) de Bordeaux

Pessac, 33604, France

RECRUITING

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

RECRUITING

Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP

Villejuif, 94805, France

RECRUITING

University Hospital Of Ulm, Universitatsklinikum Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

RECRUITING

Universitaetsklinikum Essen (AoR)

Essen, 45147, Germany

WITHDRAWN

Universitaetsmedizin Greifswald

Greifswald, 17475, Germany

COMPLETED

Universitaetsmedizin Der Johannes

Gutenberg, 55131, Germany

RECRUITING

Universitaetsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

RECRUITING

University of Leipzig

Leipzig, 04103, Germany

RECRUITING

Klinikum Nuernberg Nord

Nuremberg, 90419, Germany

COMPLETED

Rambam Health Care Campus (RHCC)

Haifa, 3109601, Israel

RECRUITING

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

RECRUITING

Hadassah Medical Center- Ein Kerem

Jerusalem, 9112001, Israel

RECRUITING

Galilee Medical Center

Nahariya, 2210010, Israel

RECRUITING

Rabin Medical Center

Petah Tikva, 4941492, Israel

RECRUITING

Sheba Medical Center

Ramat Gan, 52621, Israel

RECRUITING

IRCCS Azienda Ospedaliero Universitaria di Bologna

Bologna, 40138, Italy

RECRUITING

Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori

Meldola, 47014, Italy

RECRUITING

IRCCS-Istituto Europeo di Oncologia

Milan, 20141, Italy

RECRUITING

Universita Cattolica Fondazione Policlinico Agostino Gemelli

Roma, 00168, Italy

RECRUITING

S Bortolo Hospital AULSS 8 Berica

Vicenza, 36100, Italy

RECRUITING

Vilnius University Hospital Santaros Klinikos

Vilnius, 08661, Lithuania

RECRUITING

Princess Maxima Center for Pediatric Oncology

Utrecht, 3584 CS, Netherlands

RECRUITING

Hospital Centro Comprensivo de Cancer UPR

San Juan, 00935, Puerto Rico

RECRUITING

Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals

L'Hospitalet de Llobregat, 08908, Spain

RECRUITING

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

RECRUITING

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, 46026, Spain

RECRUITING

Related Publications (6)

• Garcia MB, Wang B, Sheikh I, El Hajjar G, McCall D, Nunez C, Gibson A, Lorenzi PL, Issa GC, Cuglievan B, Abbas HA. High-Throughput Proteomic Profiling to Evaluate Differentiation Syndrome With Menin Inhibition. Mol Cell Proteomics. 2026 Mar;25(3):101522. doi: 10.1016/j.mcpro.2026.101522. Epub 2026 Jan 30.

  PMID: 41621809 DERIVED

• Arellano ML, Thirman MJ, DiPersio JF, Heiblig M, Stein EM, Schuh AC, Zucenka A, de Botton S, Grove CS, Mannis GN, Papayannidis C, Perl AE, Issa GC, Aldoss I, Bajel A, Dickens DS, Kuhn MWM, Mantzaris I, Raffoux E, Traer E, Amitai I, Dohner H, Greco C, Kovacsovics T, McMahon CM, Montesinos P, Pigneux A, Shami PJ, Stone RM, Wolach O, Harpel JG, Chudnovsky Y, Yu L, Bagley RG, Smith AR, Blachly JS. Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study. Blood. 2025 Aug 28;146(9):1065-1077. doi: 10.1182/blood.2025028357.

  PMID: 40332046 DERIVED

• Issa GC, Aldoss I, Thirman MJ, DiPersio J, Arellano M, Blachly JS, Mannis GN, Perl A, Dickens DS, McMahon CM, Traer E, Zwaan CM, Grove CS, Stone R, Shami PJ, Mantzaris I, Greenwood M, Shukla N, Cuglievan B, Kovacsovics T, Gu Y, Bagley RG, Madigan K, Chudnovsky Y, Nguyen HV, McNeer N, Stein EM. Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). J Clin Oncol. 2025 Jan;43(1):75-84. doi: 10.1200/JCO.24.00826. Epub 2024 Aug 9.

  PMID: 39121437 DERIVED

• Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023 Mar;615(7954):920-924. doi: 10.1038/s41586-023-05812-3. Epub 2023 Mar 15.

  PMID: 36922593 DERIVED

• Sasca D, Guezguez B, Kuhn MWM. Next generation epigenetic modulators to target myeloid neoplasms. Curr Opin Hematol. 2021 Sep 1;28(5):356-363. doi: 10.1097/MOH.0000000000000673.

  PMID: 34267079 DERIVED

• Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19.

  PMID: 33741715 DERIVED

Related Links

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MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute; Leukemia

Interventions

revumenib; Cobicistat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Angela R Smith, M.D.

  Syndax Pharmaceuticals

  STUDY DIRECTOR

Central Study Contacts

Syndax Pharmaceuticals

CONTACT

781-419-1400; clinicaltrials@syndax.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: Phase 1 will employ an accelerated titration design. The dose escalation will follow a modified Fibonacci sequence.

Study Record Dates

• First Submitted: August 16, 2019
• First Posted: August 22, 2019
• Study Start: November 5, 2019
• Primary Completion (Estimated): December 15, 2027
• Study Completion (Estimated): December 15, 2027
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5); CA (2); NL (1); ES (3); IL (6); PR (1); DE (7); FR (4); IT (5); US (22); LI (1)