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

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

Overview

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)

Interventions

• Drug revumenib
  revumenib orally
• Drug cobicistat
  Phase 1 Arm C participants will receive 150 mg cobicistat daily.

Primary outcome measures

• Number of participants with dose-limiting toxicities (DLTs) (Phase 1) [Time frame: Approximately 1 year]
• Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1) [Time frame: Approximately 1 year]
• Cmax (Phase 1) [Time frame: Approximately 1 year]
• Tmax (Phase 1) [Time frame: Approximately 1 year]
• AUC0-t (Phase 1) [Time frame: Approximately 1 year]
• CR+CRh rate (Phase 2 [Cohorts 2A-2C]) [Time frame: Approximately 3 years]
• Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C]) [Time frame: Approximately 3 years]
• Cmax (Phase 2 [Cohort 2D]) [Time frame: Approximately 3 years]
• AUC0-tau (Phase 2 [Cohort 2D]) [Time frame: Approximately 3 years]

Secondary outcome measures (11)

• 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

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.

• 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.
• 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.
• 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. 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.
• 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.

Phase 1 and Phase 2 Cohorts 2A-2C only:

• 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).
• 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.
• 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.
• Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy.
• 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.
• Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent.
• 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:

• 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.
• Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician's discretion.
• 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.
• Adequate organ function.
• 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.

Exclusion criteria

Participants meeting any of the following criteria are not eligible for study participation:

• Diagnosis of active acute promyelocytic leukemia.
• Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 22 centers

• City of Hope Comprehensive Cancer Center — Duarte
• University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospi — Los Angeles
• Stanford Cancer Institute — Palo Alto
• University of Colorado — Aurora
• Florida Cancer Specialists and Research Institute — Sarasota
• Moffitt Cancer Center — Tampa
• Emory Winship Cancer Institute — Atlanta
• Children's Healthcare of Atlanta — Atlanta
• … and 14 more centers

Germany · 7 centers

• University Hospital Of Ulm, Universitatsklinikum Ulm — Ulm
• Universitaetsklinikum Essen (AoR) — Essen
• Universitaetsmedizin Greifswald — Greifswald
• Universitaetsmedizin Der Johannes — Gutenberg
• Universitaetsklinikum Hamburg-Eppendorf — Hamburg
• University of Leipzig — Leipzig
• Klinikum Nuernberg Nord — Nuremberg

Israel · 6 centers

• Rambam Health Care Campus (RHCC) — Haifa
• Shaare Zedek Medical Center — Jerusalem
• Hadassah Medical Center- Ein Kerem — Jerusalem
• Galilee Medical Center — Nahariya
• Rabin Medical Center — Petah Tikva
• Sheba Medical Center — Ramat Gan

Australia · 5 centers

• Peter MacCallum Cancer Centre (PMCC) — Melbourne
• Royal Melbourne Hospital (RMH) — Parkville
• Alfred Hospital — Melbourne
• Sir Charles Gairdner Hospital — Nedlands
• Royal North Shore Hospital — Saint Leonards

Italy · 5 centers

• IRCCS Azienda Ospedaliero Universitaria di Bologna — Bologna
• Istituto Romagnolo Per Lo Studio dei tumori Dino Amadori — Meldola
• IRCCS-Istituto Europeo di Oncologia — Milan
• Universita Cattolica Fondazione Policlinico Agostino Gemelli — Roma
• S Bortolo Hospital AULSS 8 Berica — Vicenza

France · 4 centers

• Hospital Saint-Louis - APHP — Paris
• Centre Hospitalier Universitaire (CHU) de Bordeaux — Pessac
• Centre Hospitalier Lyon Sud — Pierre-Bénite
• Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP — Villejuif

Spain · 3 centers

• Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals — L'Hospitalet de Llobregat
• Hospital Universitario Virgen del Rocio — Seville
• Hospital Universitari i Politecnic La Fe de Valencia — Valencia

Canada · 2 centers

• University Health Network — Toronto
• The Hospital for Sick Children — Toronto

Lithuania · 1 center

• Vilnius University Hospital Santaros Klinikos — Vilnius

Netherlands · 1 center

• Princess Maxima Center for Pediatric Oncology — Utrecht

Puerto Rico · 1 center

• Hospital Centro Comprensivo de Cancer UPR — San Juan

Publications

• Garcia MB, Wang B, Sheikh I, El Hajjar G, McCall D, Nunez C, Gibson A, Lorenzi PL, Issa GC, Cuglievan B, Abbas HA. High-Throughput Proteomic Profiling to Evaluate Differentiation Syndrome With Menin Inhibition. Mol Cell Proteomics. 2026 Mar;25(3):101522. doi: 10.1016/j.mcpro.2026.101522. Epub 2026 Jan 30. PMID 41621809
• Arellano ML, Thirman MJ, DiPersio JF, Heiblig M, Stein EM, Schuh AC, Zucenka A, de Botton S, Grove CS, Mannis GN, Papayannidis C, Perl AE, Issa GC, Aldoss I, Bajel A, Dickens DS, Kuhn MWM, Mantzaris I, Raffoux E, Traer E, Amitai I, Dohner H, Greco C, Kovacsovics T, McMahon CM, Montesinos P, Pigneux A, Shami PJ, Stone RM, Wolach O, Harpel JG, Chudnovsky Y, Yu L, Bagley RG, Smith AR, Blachly JS. Men PMID 40332046
• Issa GC, Aldoss I, Thirman MJ, DiPersio J, Arellano M, Blachly JS, Mannis GN, Perl A, Dickens DS, McMahon CM, Traer E, Zwaan CM, Grove CS, Stone R, Shami PJ, Mantzaris I, Greenwood M, Shukla N, Cuglievan B, Kovacsovics T, Gu Y, Bagley RG, Madigan K, Chudnovsky Y, Nguyen HV, McNeer N, Stein EM. Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). PMID 39121437
• Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023 Mar;615(7954):920-924. doi: 10.1038/s41586-023-05812 PMID 36922593
• Sasca D, Guezguez B, Kuhn MWM. Next generation epigenetic modulators to target myeloid neoplasms. Curr Opin Hematol. 2021 Sep 1;28(5):356-363. doi: 10.1097/MOH.0000000000000673. PMID 34267079
• Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19. PMID 33741715

Identifiers

NCT: NCT04065399 · SNDX-5613-0700 · 2020-004104-34

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗