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RecruitingInterventionalPhase 1/Phase 2

A Phase 1/2, Open-label, Dose-Escalation and Dose-Expansion Cohort Study of SNDX-5613 in Patients With Relapsed/Refractory Leukemias, Including Those Harboring an MLL/KMT2A Gene Rearrangement or Nucleophosmin 1 (NPM1) Mutation

NCT ID: NCT04065399Sponsor: Syndax PharmaceuticalsLast updated: 2026-03-18

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.

Detailed description

Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms: Arm A: Participants not receiving any strong cytochrome P450 3A4 (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 and cobicistat. Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers. Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. 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: * Cohort 2A: Participants with KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL) * Cohort 2B: Participants with KMT2A 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)

Arms & interventions

  • Drugrevumenib

    revumenib orally

  • Drugcobicistat

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

Outcome measures

Primary

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

    Assessed by the NCI CTCAE version 5.0 (Phase 1)

    Time frame: Approximately 1 year

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

    Assessed by the NCI CTCAE version 5.0 (Phase 1)

    Time frame: Approximately 1 year

  • Cmax (Phase 1)

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

    Time frame: Approximately 1 year

  • Tmax (Phase 1)

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

    Time frame: 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)

    Time frame: 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 \[Cohorts 2A-2C\])

    Time frame: Approximately 3 years

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

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

    Time frame: Approximately 3 years

  • Cmax (Phase 2 [Cohort 2D])

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

    Time frame: 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 \[Cohort 2D\])

    Time frame: Approximately 3 years

Secondary

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

    Time frame: Approximately 3 years

  • CRc rate (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

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

    Time frame: Approximately 3 years

  • TTR (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 34 months

  • DOR (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

  • EFS (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

  • OS (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 5 years

  • Cmax (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

  • Tmax (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

  • AUC0-t (Phase 2 [Cohorts 2A-2C])

    Time frame: Approximately 3 years

  • Number of participants with TEAEs (Phase 2 [Cohort 2D])

    Time frame: Approximately 3 years

Eligibility criteria

Sex: AllAge: 30 Days and olderHealthy volunteers: No
Key Inclusion Criteria: 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. 1. 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. 2. 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. 3. White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria. 4. Male or female participants aged ≥30 days old. Participants intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kilograms (kg). Participants in Cohort 2D must be ≥18 years of age and have a body weight ≥40 kg. 5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥50. 6. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia. Phase 1 and Phase 2 Cohorts 2A-2C only: 7. Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port). 8. Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion. 9. Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T or NK cell therapy. 10. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy. 11. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors. 12. Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent. 13. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing or cytoreductive therapy. Phase 2 Cohort 2D only: At least 14 days since any other investigational or commercially available antileukemic therapy, with the following exceptions: 1. Cytoreductive therapy with hydroxyurea, low-dose cytarabine (20 mg/square meter (m\^2)/day subcutaneously \[SC\] for 10 days) or low-dose etoposide (up to 200 mg/day orally for 10 days) may be administered concurrently with SNDX-5613. 2. Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician's discretion. 3. Steroids at physiologic dosing (equivalent to ≤10 mg prednisone daily for participants ≥18 years or ≤10 mg/m\^2/day for participants \<18 years) or for cytoreductive therapy. 14. Adequate organ function. 15. If of childbearing potential, willing to use a highly effective method of contraception from the time of enrollment through 120 days following the last study drug dose. Key Exclusion Criteria: Participants meeting any of the following criteria are not eligible for study participation: 1. Diagnosis of active acute promyelocytic leukemia. 2. Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C only). 3. Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic). 4. 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. 5. Hepatitis B or C. 6. Pregnant or nursing women. 7. 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. 8. 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. 9. 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. 10. 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. 11. In Phase 1 and Phase 2: Participants requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (for example, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the relevant arms of Phase 1 and in Phase 2. Note: Other protocol defined inclusion/exclusion criteria may apply.

Study locations (22)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010

Active Not Recruiting

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

Los Angeles, California, 90033

Completed

Stanford Cancer Institute

Palo Alto, California, 94305

Active Not Recruiting

University of Colorado

Aurora, Colorado, 80045

Recruiting
Katelyn Anttila · Contact
Christine McMahon · Principal Investigator

Florida Cancer Specialists and Research Institute

Sarasota, Florida, 34232

Active Not Recruiting

Moffitt Cancer Center

Tampa, Florida, 33162

Completed

Emory Winship Cancer Institute

Atlanta, Georgia, 30322

Recruiting
Feranmi Arowolo · Contact
Martha Arellano · Principal Investigator

Children's Healthcare of Atlanta

Atlanta, Georgia, 30329

Completed

The University of Chicago Medical Center

Chicago, Illinois, 60637

Recruiting
Ellen Malone · Contact
Michael Thirman · Principal Investigator

University of Iowa Hospital

Iowa City, Iowa, 52246

Recruiting
Chris Stamy · Contact
David Dickens, MD · Principal Investigator

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

Active Not Recruiting

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110

Recruiting
Morgan Swanner · Contact
John DiPersio · Principal Investigator

Hackensack University Medical Center

Hackensack, New Jersey, 07601

Completed

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Active Not Recruiting

Montefiore Medical Center

New York, New York, 10467

Recruiting
Aradhika Dhawan · Contact
Ioannis Mantzaris · Principal Investigator

Duke University Medical Center

Durham, North Carolina, 27110

Recruiting
Linda Brown · Contact
Brittany DePriest · Principal Investigator

University of Cincinnati

Cincinnati, Ohio, 45267

Completed

Ohio State University

Columbus, Ohio, 43201

Recruiting
Sarah Mayne · Contact
James Blachly · Principal Investigator

Oregon Health & Science University

Portland, Oregon, 97239

Recruiting
OHSU Knight Cancer Institute Clinical Trials · Contact
Elie Traer, MD · Principal Investigator

University of Pennsylvania

Philadelphia, Pennsylvania, 19104

Recruiting
Robin E Blauser, BSN RN · Contact
Thomas Greenwood · Contact
Alexander Perl · Principal Investigator

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030

Active Not Recruiting

Huntsman Cancer Institute at the University of Utah

Salt Lake City, Utah, 84112

Completed

References

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