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A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation
NCT04065399 · Syndax Pharmaceuticals
In plain English
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Official title
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
About this study
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
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 design
Enrollment target: 447 participants
Allocation: na
Masking: none
Age groups: child, adult, older_adult
Timeline
Starts: 2019-11-05
Estimated completion: 2027-12-15
Last updated: 2026-09-16
Interventions
Drug: revumenibDrug: cobicistat
Primary outcomes
- • Number of participants with dose-limiting toxicities (DLTs) (Phase 1) (Approximately 1 year)
- • Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1) (Approximately 1 year)
- • Cmax (Phase 1) (Approximately 1 year)
Sponsor
Syndax Pharmaceuticals · industry
Contacts & investigators
ContactSyndax Pharmaceuticals · contact · clinicaltrials@syndax.com · 781-419-1400
InvestigatorAngela R Smith, M.D. · study_director, Syndax Pharmaceuticals
All locations (57)
City of Hope Comprehensive Cancer CenterActive Not Recruiting
Duarte, California, United States
University Of California Care Medical Group - Norris Comprehensive Cancer Center And HospitalCompleted
Los Angeles, California, United States
Stanford Cancer InstituteActive Not Recruiting
Palo Alto, California, United States
University of ColoradoRecruiting
Aurora, Colorado, United States
Florida Cancer Specialists and Research InstituteActive Not Recruiting
Sarasota, Florida, United States
Moffitt Cancer CenterCompleted
Tampa, Florida, United States
Emory Winship Cancer InstituteRecruiting
Atlanta, Georgia, United States
Children's Healthcare of AtlantaCompleted
Atlanta, Georgia, United States
The University of Chicago Medical CenterRecruiting
Chicago, Illinois, United States
University of Iowa HospitalRecruiting
Iowa City, Iowa, United States
Dana Farber Cancer InstituteActive Not Recruiting
Boston, Massachusetts, United States
Washington University in St. Louis School of MedicineRecruiting
St Louis, Missouri, United States
Hackensack University Medical CenterCompleted
Hackensack, New Jersey, United States
Memorial Sloan Kettering Cancer CenterActive Not Recruiting
New York, New York, United States
Montefiore Medical CenterRecruiting
New York, New York, United States
Duke University Medical CenterRecruiting
Durham, North Carolina, United States
University of CincinnatiCompleted
Cincinnati, Ohio, United States
Ohio State UniversityRecruiting
Columbus, Ohio, United States
Oregon Health & Science UniversityRecruiting
Portland, Oregon, United States
University of PennsylvaniaRecruiting
Philadelphia, Pennsylvania, United States
The University of Texas MD Anderson Cancer CenterActive Not Recruiting
Houston, Texas, United States
Huntsman Cancer Institute at the University of UtahCompleted
Salt Lake City, Utah, United States
Peter MacCallum Cancer Centre (PMCC)Active Not Recruiting
Melbourne, Victoria, Australia
Royal Melbourne Hospital (RMH)Active Not Recruiting
Parkville, Victoria, Australia
Alfred HospitalRecruiting
Melbourne, Australia
Sir Charles Gairdner HospitalRecruiting
Nedlands, Australia
Royal North Shore HospitalRecruiting
Saint Leonards, Australia
University Health NetworkRecruiting
Toronto, Canada
The Hospital for Sick ChildrenActive Not Recruiting
Toronto, Canada
Hospital Saint-Louis - APHPRecruiting
Paris, France
Centre Hospitalier Universitaire (CHU) de BordeauxRecruiting
Pessac, France
Centre Hospitalier Lyon SudRecruiting
Pierre-Bénite, France
Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEPRecruiting
Villejuif, France
University Hospital Of Ulm, Universitatsklinikum UlmRecruiting
Ulm, Baden-Wurttemberg, Germany
Universitaetsklinikum Essen (AoR)Withdrawn
Essen, Germany
Universitaetsmedizin GreifswaldCompleted
Greifswald, Germany
Universitaetsmedizin Der JohannesRecruiting
Gutenberg, Germany
Universitaetsklinikum Hamburg-EppendorfRecruiting
Hamburg, Germany
University of LeipzigRecruiting
Leipzig, Germany
Klinikum Nuernberg NordCompleted
Nuremberg, Germany
Rambam Health Care Campus (RHCC)Recruiting
Haifa, Israel
Shaare Zedek Medical CenterRecruiting
Jerusalem, Israel
Hadassah Medical Center- Ein KeremRecruiting
Jerusalem, Israel
Galilee Medical CenterRecruiting
Nahariya, Israel
Rabin Medical CenterRecruiting
Petah Tikva, Israel
Sheba Medical CenterRecruiting
Ramat Gan, Israel
IRCCS Azienda Ospedaliero Universitaria di BolognaRecruiting
Bologna, Italy
Istituto Romagnolo Per Lo Studio dei tumori Dino AmadoriRecruiting
Meldola, Italy
IRCCS-Istituto Europeo di OncologiaRecruiting
Milan, Italy
Universita Cattolica Fondazione Policlinico Agostino GemelliRecruiting
Roma, Italy
S Bortolo Hospital AULSS 8 BericaRecruiting
Vicenza, Italy
Vilnius University Hospital Santaros KlinikosRecruiting
Vilnius, Lithuania
Princess Maxima Center for Pediatric OncologyNot Yet Recruiting
Utrecht, Netherlands
Hospital Centro Comprensivo de Cancer UPRRecruiting
San Juan, Puerto Rico
Institut Catala d'Oncologia (ICO) - Hospital Duran i ReynalsRecruiting
L'Hospitalet de Llobregat, Spain
Hospital Universitario Virgen del RocioRecruiting
Seville, Spain
Hospital Universitari i Politecnic La Fe de ValenciaRecruiting
Valencia, Spain