P-213: 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: Trial in Progress. Menin, a protein involved in transcriptional regulation, 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 cell lines including acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) representing Double/Triple Hit Lymphoma (DHL/THL) & Double Expressor Lymphoma (DEL), multiple myeloma (MM) 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 CLL patient specimens with various cytogenetic backgrounds.

Methods: COVALENT-101 is a prospective, open-label, multi-cohort, non-randomized, Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of 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, the optimal biological dose/recommended Phase 2 dose of BMF-219 monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of antitumor activity based on best overall response rate, duration of response, progression-free survival, and time to progression. Food-effect studies will be performed at certain dose levels.
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. At that point, the cohort will switch to a classical “3 + 3” design. Treatment continues in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will be enrolled 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 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 2023 the study is enrolling at 16 sites in the United States, Spain and the Netherlands. Other European sites in Greece, Italy and France are in startup.

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