NCT04065399 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE1, PHASE2
Status at capture: RECRUITING
Registry last update: 2026-03-18

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

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.
healthy Volunteers: false
minimum Age: 30 Days
sex: ALL
std Ages: CHILD
ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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)
intervention Names
Drug: revumenib
Drug: cobicistat
label
Revumenib
type
EXPERIMENTAL

interventions

arm Group Labels
Revumenib
description
revumenib orally
name
revumenib
other Names
SNDX-5613
type
DRUG
arm Group Labels
Revumenib
description
Phase 1 Arm C participants will receive 150 mg cobicistat daily.
name
cobicistat
type
DRUG

Study design

allocation

intervention Model

SEQUENTIAL

intervention Model Description

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

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 447
type: ESTIMATED

Registered outcome plans (not posted results)

primary Outcomes

description
Assessed by the NCI CTCAE version 5.0 (Phase 1)
measure
Number of participants with dose-limiting toxicities (DLTs) (Phase 1)
time Frame
Approximately 1 year
description
Assessed by the NCI CTCAE version 5.0 (Phase 1)
measure
Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)
time Frame
Approximately 1 year
description
Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1)
measure
Cmax (Phase 1)
time Frame
Approximately 1 year
description
Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1)
measure
Tmax (Phase 1)
time Frame
Approximately 1 year
description
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)
measure
AUC0-t (Phase 1)
time Frame
Approximately 1 year
description
To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2 \[Cohorts 2A-2C\])
measure
CR+CRh rate (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohorts 2A-2C\])
measure
Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
Cmax of revumenib (Phase 2 \[Cohort 2D\])
measure
Cmax (Phase 2 [Cohort 2D])
time Frame
Approximately 3 years
description
Area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) of revumenib (Phase 2 \[Cohort 2D\])
measure
AUC0-tau (Phase 2 [Cohort 2D])
time Frame
Approximately 3 years

secondary Outcomes

description
Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days
measure
Transfusion independence (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
To assess the composite definition of complete remission (CRc) rate (Phase 2 \[Cohorts 2A-2C\])
measure
CRc rate (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
To assess the overall response rate (ORR) of revumenib (Phase 2 \[Cohorts 2A-2C\])
measure
ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
To assess the time to response (TTR) of revumenib (Phase 2 \[Cohorts 2A-2C\])
measure
TTR (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 34 months
description
To assess the duration of response (DOR) of revumenib (Phase 2 \[Cohorts 2A-2C\])
measure
DOR (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
To assess the event free survival (EFS) of revumenib (Phase 2 \[Cohorts 2A-2C\])
measure
EFS (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
To assess overall survival (OS) of revumenib (Phase 2 \[Cohorts 2A-2C\])
measure
OS (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 5 years
description
Cmax of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\])
measure
Cmax (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
Tmax of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\])
measure
Tmax (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
AUC0-t of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\])
measure
AUC0-t (Phase 2 [Cohorts 2A-2C])
time Frame
Approximately 3 years
description
Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohort 2D\]))
measure
Number of participants with TEAEs (Phase 2 [Cohort 2D])
time Frame
Approximately 3 years

Full study description

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.
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)

Source references

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