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
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)
Arms & interventions
- Drugrevumenib
revumenib orally
- Drugcobicistat
Phase 1 Arm C participants will receive 150 mg cobicistat daily.
Outcome measures
Primary
Number of participants with dose-limiting toxicities (DLTs) (Phase 1)
Assessed by the NCI CTCAE version 5.0 (Phase 1)
Time frame: Approximately 1 year
Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)
Assessed by the NCI CTCAE version 5.0 (Phase 1)
Time frame: Approximately 1 year
Cmax (Phase 1)
Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1)
Time frame: Approximately 1 year
Tmax (Phase 1)
Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1)
Time frame: 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)
Time frame: Approximately 1 year
CR+CRh rate (Phase 2 [Cohorts 2A-2C])
To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2 \[Cohorts 2A-2C\])
Time frame: Approximately 3 years
Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C])
Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohorts 2A-2C\])
Time frame: Approximately 3 years
Cmax (Phase 2 [Cohort 2D])
Cmax of revumenib (Phase 2 \[Cohort 2D\])
Time frame: Approximately 3 years
AUC0-tau (Phase 2 [Cohort 2D])
Area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) of revumenib (Phase 2 \[Cohort 2D\])
Time frame: Approximately 3 years
Secondary
Transfusion independence (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
CRc rate (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
TTR (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 34 months
DOR (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
EFS (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
OS (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 5 years
Cmax (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
Tmax (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
AUC0-t (Phase 2 [Cohorts 2A-2C])
Time frame: Approximately 3 years
Number of participants with TEAEs (Phase 2 [Cohort 2D])
Time frame: Approximately 3 years
Eligibility criteria
Study locations (22)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital
Los Angeles, California, 90033
Stanford Cancer Institute
Palo Alto, California, 94305
University of Colorado
Aurora, Colorado, 80045
Florida Cancer Specialists and Research Institute
Sarasota, Florida, 34232
Moffitt Cancer Center
Tampa, Florida, 33162
Emory Winship Cancer Institute
Atlanta, Georgia, 30322
Children's Healthcare of Atlanta
Atlanta, Georgia, 30329
The University of Chicago Medical Center
Chicago, Illinois, 60637
University of Iowa Hospital
Iowa City, Iowa, 52246
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Washington University in St. Louis School of Medicine
St Louis, Missouri, 63110
Hackensack University Medical Center
Hackensack, New Jersey, 07601
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Montefiore Medical Center
New York, New York, 10467
Duke University Medical Center
Durham, North Carolina, 27110
University of Cincinnati
Cincinnati, Ohio, 45267
Ohio State University
Columbus, Ohio, 43201
Oregon Health & Science University
Portland, Oregon, 97239
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Huntsman Cancer Institute at the University of Utah
Salt Lake City, Utah, 84112
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