AML-522 COVALENT-101: Phase I Study of BMF-219, a Covalent Menin Inhibitor, in Adult Patients With AML, ALL (With KMT2A/MLL1 Rearrangements, NPM1 Mutation), DLBCL, MM, and CLL/SLL (NCT05153330)

• Published in: Clinical lymphoma, myeloma and leukemia Vol. 23; pp. S310 - S311
• Main Authors: Ravandi, Farhad, Lancet, Jeffrey, Amor, Adrian Alegre, Badar, Talha, Barrientos, Jacqueline, Bashey, Asad, Burgues, Juan Miguel Bergua, Curran, Emily, Janssen, Jeroen, Jeyakumar, Deepa, Kishtagari, Ashwin, Montesinos, Pau, Morillo, Daniel, Rosenberg, Aaron, Schiller, Gary, Ahmed, Uzma, Cacovean, Alex, Morris, Steve, Follit, Courtney, Mandap, Clarissa, Butler, Thomas, Carraway, Hetty
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2023
• Subjects: acute myeloid leukemia; chronic lymphocytic leukemia; DLBCL; multiple myeloma; trial-in-progress; trial-in-progress; DLBCL; multiple myeloma; chronic lymphocytic leukemia; acute myeloid leukemia
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/S2152-2650(23)01077-7

Menin, a protein involved in transcriptional regulation, impacting cell-cycle control, apoptosis, and DNA-damage repair, plays a direct role in oncogenic signaling in multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, orally bioavailable, small-molecule covalent inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first investigational menin inhibitor in clinical development to show potential as a therapeutic agent in hematologic malignancies outside of acute leukemia (AL), specifically in subsets of diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). To determine independently, for each cohort/indication, the optimal biological dose (OBD) and recommended phase II dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of pharmacokinetics and pharmacodynamics, and assessment of antitumor activity. Phase I, prospective, open-label, nonrandomized, dose-escalation and dose-expansion study of BMF-219 in relapsed or refractory (R/R) AL, DLBCL, MM, and CLL. Using an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts, independently for each indication, until 1 patient experiences either a grade ≥2 related adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 + 3” design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data at the OBD/RP2D. Adult patients with R/R AL who have experienced standard-therapy failure or are ineligible for standard therapies, DLBCL who received at least 2 prior therapies, MM who received at least 3 prior therapies, and CLL/SLL who received at least 2 prior therapies. Escalation phase: Patients will receive escalating doses of BMF-219 orally once per day in continuous 28-day cycles to identify the OBD/RP2D for each cohort/indication. Alternative twice daily dosing may be used. Expansion phase: BMF-219 will be administered orally at the OBD/ RP2D. Primary: Incidence of DLTs, treatment-emergent adverse events, and serious adverse events. Secondary: Best overall response rate, duration of response, progression-free survival, and time to progression per disease-specific response criteria.