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

PHASE1PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.

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).

White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria.

Male or female participants aged ≥30 days old.

Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥50.

Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.

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).

At least 60 days must have elapsed from hematopoietic stem cell transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.

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.

At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy.

At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.

At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent.

At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing or cytoreductive therapy.

Adequate organ function.

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.

Exclusion criteria

Diagnosis of active acute promyelocytic leukemia.

Isolated extramedullary relapse (Phase 2 only).

Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic).

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.

Hepatitis B or C.

Pregnant or nursing women.

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.

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.

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.

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.

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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Eligibility

Age eligible for study : 30 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2019-11-05

Primary completion: 2024-12-01

Study completion finish: 2024-12-01

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT04065399

Intervention or treatment

DRUG: revumenib

DRUG: cobicistat

Conditions

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Mixed Phenotype Acute Leukemia
• Mixed Lineage Acute Leukemia
• Acute Leukemia of Ambiguous Lineage

Condition: Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia and more
DRUG: revumenib and other drugs
Melbourne, Not Specified, Australia and more
Sponsor: Syndax Pharmaceuticals

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

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Find a site

Closest Location:

Alfred Hospital

Research sites nearby

Select from list below to view details:

Alfred Hospital
Melbourne, Not Specified, Australia
Peter MacCallum Cancer Centre (PMCC)
Melbourne, Victoria, Australia
Royal Melbourne Hospital (RMH)
Parkville, Victoria, Australia
Sir Charles Gairdner Hospital
Nedlands, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 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	DRUG: revumenib revumenib orally

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: 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

DRUG: revumenib

revumenib orally

What is the study measuring?

Primary outcome

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

Secondary outcome

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

Frequently Asked Questions

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References

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