3003 - COVALENT-101: Phase I Study of BMF-219, a Covalent Menin Inhibitor, in Adult Patients With AML, ALL (With KMT2A/ MLL1r, NPM1 Mutations), DLBCL, MM, and CLL/SLL (NCT05153330)

Introduction: 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. Inhibition of menin is therefore a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule covalent inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, diffuse large B-cell lymphoma (DLBCL) cell lines representing Double/Triple Hit Lymphoma (DHL/THL) & Double Expressor Lymphoma (DEL), multiple myeloma (MM) cell lines with diverse mutational backgrounds.

BMF-219 also exhibits high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, bone marrow mononuclear cells from treatment-naive and R/R MM, and a collection of CLL patient specimens with various cytogenetic backgrounds including TP53 and NOTCH1 mutations, & previous BTK inhibitor therapy.

Aims: COVALENT-101 (NCT05153330) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of daily oral BMF-219 in patients with relapsed or refractory (R/R) acute leukemia (AL), DLBCL, MM and CLL who have received standard therapy. The primary objective of the study is to determine independently for each cohort/indication, the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed at certain dose levels.

Methods: Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject 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. Patients with R/R AL, DLBCL who received at least 2 prior therapies, MM who received at least 3 prior therapies, CLL/SLL who received at least 2 prior therapies and have either failed or are ineligible for any standard therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, and clinically significant cardiovascular disease.

Results: As of May 20, 2023, the study is currently enrolling at 16 sites in the United States, Spain, and the Netherlands. Other European sites in Greece, Italy and France are in startup.

Conclusion: Enrollment commenced in January 2022 in the United States and in May 2023 in Europe.