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NCT04065399PHASE1, PHASE2Recruiting

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

Syndax Pharmaceuticals

Start Date

11/5/2019

Completion Date

12/15/2027

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)

Eligibility Criteria

Age Range: No minimum to No maximum

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.

Interventions

DRUG

revumenib

DRUG

cobicistat

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Conditions

Acute Myeloid LeukemiaAcute Lymphoblastic LeukemiaMixed Lineage Acute LeukemiaMixed Phenotype Acute LeukemiaAcute Leukemia of Ambiguous Lineage

Locations

City of Hope Comprehensive Cancer Center

Duarte, California 91010

United States

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

Los Angeles, California 90033

United States

Stanford Cancer Institute

Palo Alto, California 94305

United States

University of Colorado

Aurora, Colorado 80045

United States

Florida Cancer Specialists and Research Institute

Sarasota, Florida 34232

United States

Moffitt Cancer Center

Tampa, Florida 33162

United States

Emory Winship Cancer Institute

Atlanta, Georgia 30322

United States

Children's Healthcare of Atlanta

Atlanta, Georgia 30329

United States

The University of Chicago Medical Center

Chicago, Illinois 60637

United States

University of Iowa Hospital

Iowa City, Iowa 52246

United States

Dana Farber Cancer Institute

Boston, Massachusetts 02215

United States

Washington University in St. Louis School of Medicine

St Louis, Missouri 63110

United States

Hackensack University Medical Center

Hackensack, New Jersey 07601

United States

Memorial Sloan Kettering Cancer Center

New York, New York 10065

United States

Montefiore Medical Center

New York, New York 10467

United States

Duke University Medical Center

Durham, North Carolina 27110

United States

University of Cincinnati

Cincinnati, Ohio 45267

United States

Ohio State University

Columbus, Ohio 43201

United States

Oregon Health & Science University

Portland, Oregon 97239

United States

University of Pennsylvania

Philadelphia, Pennsylvania 19104

United States

The University of Texas MD Anderson Cancer Center

Houston, Texas 77030

United States

Huntsman Cancer Institute at the University of Utah

Salt Lake City, Utah 84112

United States

Peter MacCallum Cancer Centre (PMCC)

Melbourne, Victoria 3000

Australia

Royal Melbourne Hospital (RMH)

Parkville, Victoria 3050

Australia

Alfred Hospital

Melbourne, 3004

Australia

Sir Charles Gairdner Hospital

Nedlands, 6009

Australia

Royal North Shore Hospital

Saint Leonards, 2065

Australia

University Health Network

Toronto, M5G 2M9

Canada

The Hospital for Sick Children

Toronto,

Canada

Hospital Saint-Louis - APHP

Paris, 75010

France

Centre Hospitalier Universitaire (CHU) de Bordeaux

Pessac, 33604

France

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495

France

Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP

Villejuif, 94805

France

University Hospital Of Ulm, Universitatsklinikum Ulm

Ulm, Baden-Wurttemberg 89081

Germany

Universitaetsklinikum Essen (AoR)

Essen, 45147

Germany

Universitaetsmedizin Greifswald

Greifswald, 17475

Germany

Universitaetsmedizin Der Johannes

Gutenberg, 55131

Germany

Universitaetsklinikum Hamburg-Eppendorf

Hamburg, 20246

Germany

University of Leipzig

Leipzig, 04103

Germany

Klinikum Nuernberg Nord

Nuremberg, 90419

Germany

Rambam Health Care Campus (RHCC)

Haifa, 3109601

Israel

Shaare Zedek Medical Center

Jerusalem, 9103102

Israel

Hadassah Medical Center- Ein Kerem

Jerusalem, 9112001

Israel

Galilee Medical Center

Nahariya, 2210010

Israel

Rabin Medical Center

Petah Tikva, 4941492

Israel

Sheba Medical Center

Ramat Gan, 52621

Israel

IRCCS Azienda Ospedaliero Universitaria di Bologna

Bologna, 40138

Italy

Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori

Meldola, 47014

Italy

IRCCS-Istituto Europeo di Oncologia

Milan, 20141

Italy

Universita Cattolica Fondazione Policlinico Agostino Gemelli

Roma, 00168

Italy

S Bortolo Hospital AULSS 8 Berica

Vicenza, 36100

Italy

Vilnius University Hospital Santaros Klinikos

Vilnius, 08661

Lithuania

Princess Maxima Center for Pediatric Oncology

Utrecht, 3584 CS

Netherlands

Hospital Centro Comprensivo de Cancer UPR

San Juan, 00935

Puerto Rico

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

L'Hospitalet de Llobregat, 08908

Spain

Hospital Universitario Virgen del Rocio

Seville, 41013

Spain

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, 46026

Spain