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

Phase 1

Recruiting

• Conditions: Mixed Phenotype Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Mixed Lineage Acute Leukemia; Acute Leukemia of Ambiguous Lineage
• Interventions: Drug: revumenib; Drug: cobicistat

• Registration Number: NCT04065399
• Lead Sponsor: Syndax Pharmaceuticals

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 3 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 3 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

Study Timeline

• Study First Submitted: 2019-08-16
• Study First Submitted QC: 2019-08-20
• Study First Posted: 2019-08-22
• Study Start: 2019-11-05
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-19
• Last Update Posted: 2024-11-21
• Primary Completion: 2027-12-15
• Study Completion: 2027-12-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 413

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.

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.

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.

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.

14. Adequate organ function.

15. If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.

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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 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, gastroparesis, etc).
   • 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Revumenib	revumenib	Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. 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; Following the determination of the RP2D in Phase 1, 3 indication-specific expansion cohorts will be enrolled as follows: * Cohort 2A: Participants with KMT2Ar ALL/MPAL * Cohort 2B: Participants with KMT2Ar AML * Cohort 2C: Participants with NPM1m AML
Revumenib	cobicistat	Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. 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; Following the determination of the RP2D in Phase 1, 3 indication-specific expansion cohorts will be enrolled as follows: * Cohort 2A: Participants with KMT2Ar ALL/MPAL * Cohort 2B: Participants with KMT2Ar AML * Cohort 2C: Participants with NPM1m AML

Primary Outcome Measures

Name	Time	Method
Cmax (Phase 1)	Approximately 1 year	Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1)
Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)	Approximately 1 year	Assessed by the NCI CTCAE version 5.0 (Phase 1)
Tmax (Phase 1)	Approximately 1 year	Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1)
Occurrence of dose-limiting toxicities (DLTs) (Phase 1)	Approximately 1 year	Assessed by the NCI CTCAE version 5.0 (Phase 1)
AUC0-t (Phase 1)	Approximately 1 year	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)
CR+CRh rate (Phase 2)	Approximately 3 years	To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2)
Number of participants with TEAEs (Phase 2)	Approximately 3 years	Assessed by the NCI CTCAE version 5.0 (Phase 2)

Secondary Outcome Measures

Name	Time	Method
OS (Phase 2)	Approximately 5 years	To assess overall survival (OS) of revumenib (Phase 2)
Tmax (Phase 2)	Approximately 3 years	Tmax of revumenib and relevant metabolites (Phase 2)
Cmax (Phase 2)	Approximately 3 years	Cmax of revumenib and relevant metabolites (Phase 2)
Transfusion independence (Phase 2)	Approximately 3 years	Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days
TTR (Phase 2)	Approximately 34 months	To assess the time to response (TTR) of revumenib (Phase 2)
DOR (Phase 2)	Approximately 3 years	To assess the duration of response (DOR) of revumenib (Phase 2)
CRc rate (Phase 2)	Approximately 3 years	To assess the composite definition of complete remission (CRc) rate (Phase 2)
ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2)	Approximately 3 years	To assess the overall response rate (ORR) of revumenib (Phase 2)
EFS (Phase 2)	Approximately 3 years	To assess the event free survival (EFS) of revumenib (Phase 2)
AUC0-t (Phase 2)	Approximately 3 years	AUC0-t of revumenib and relevant metabolites (Phase 2)

Trial Locations

Locations (57)

Hospital Saint-Louis - APHP; 🇫🇷 Paris, France

Centre Hospitalier Universitaire (CHU) de Bordeaux; 🇫🇷 Pessac, France

University Hospital Of Ulm, Universitatsklinikum Ulm; 🇩🇪 Ulm, Baden-Württemberg, Germany

Universitaetsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

University of Leipzig; 🇩🇪 Leipzig, Germany

Klinikum Nuernberg Nord; 🇩🇪 Nürnberg, Germany

IRCCS-Istituto Europeo di Oncologia; 🇮🇹 Milan, Italy

Universita Cattolica Fondazione Policlinico Agostino Gemelli; 🇮🇹 Roma, Italy

Hospital Centro Comprensivo de Cancer UPR; 🇵🇷 San Juan, Puerto Rico

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital; 🇺🇸 Los Angeles, California, United States

Stanford Cancer Institute; 🇺🇸 Palo Alto, California, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

Florida Cancer Specialists and Research Institute; 🇺🇸 Sarasota, Florida, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Emory Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

The University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

University of Iowa hospital; 🇺🇸 Iowa City, Iowa, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Washington University in St. Louis School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Montefiore Medical Center; 🇺🇸 New York, New York, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

University of Cincinnati; 🇺🇸 Cincinnati, Ohio, United States

Ohio State University; 🇺🇸 Columbus, Ohio, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Huntsman Cancer Institute at the University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Peter MacCallum Cancer Centre (PMCC); 🇦🇺 Melbourne, Victoria, Australia

Royal Melbourne Hospital (RMH); 🇦🇺 Parkville, Victoria, Australia

Alfred Hospital; 🇦🇺 Melbourne, Australia

Sir Charles Gairdner Hospital; 🇦🇺 Nedlands, Australia

Royal North Shore Hospital; 🇦🇺 Saint Leonards, Australia

University Health Network; 🇨🇦 Toronto, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Canada

Centre Hospitalier Lyon Sud; 🇫🇷 Pierre-Benite, France

Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP; 🇫🇷 Villejuif, France

Universitaetsklinikum Essen (AoR); 🇩🇪 Essen, Germany

Universitaetsmedizin Greifswald; 🇩🇪 Greifswald, Germany

Universitaetsmedizin Der Johannes; 🇩🇪 Gutenberg, Germany

Rambam Health Care Campus (RHCC; 🇮🇱 Haifa, Israel

Shaare Zedek Medical Center; 🇮🇱 Jerusalem, Israel

Hadassah Medical Center- Ein Kerem; 🇮🇱 Jerusalem, Israel

Galilee Medical Center; 🇮🇱 Nahariya, Israel

Rabin Medical Center; 🇮🇱 Petach Tikva, Israel

Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

IRCCS Azienda Ospedaliero Universitaria di Bologna; 🇮🇹 Bologna, Italy

Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori; 🇮🇹 Meldola, Italy

S Bortolo Hospital AULSS 8 Berica; 🇮🇹 Vicenza, Italy

Vilnius University Hospital Santaros Klinikos; 🇱🇹 Vilnius, Lithuania

Princess Maxima Center for Pediatric Oncology; 🇳🇱 Utrecht, Netherlands

Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals; 🇪🇸 Hospitalet De Llobregat, Spain

Hospital Universitario Virgen del Rocio; 🇪🇸 Seville, Spain

Hospital Universitari i Politecnic La Fe de Valencia; 🇪🇸 Valencia, Spain