Abstract
Abstract Background: 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 a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 demonstrated a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, DLBCL lines representing Double/Triple Hit Lymphoma (DHL/THL), Double Expressor Lymphoma (DEL), and MM cell lines harboring diverse mutational backgrounds. BMF-219 also exhibited high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM. Methods: BF-MNN-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 oral BMF-219 administered once daily in patients with R/R AL, DLBCL and MM who have received standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication following a modified Fibonacci sequence until 1 subject experiences either a ≥ Grade 2 adverse event or dose limiting toxicity (DLT). At that point, the current and all subsequent dose level(s) for the specific indication/cohort will follow a classical “3 + 3” design. Each treatment cycle will be 28 days until progression or intolerability occurs. Following conclusion of the parallel dose-escalations, expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Eligible patients include those with R/R AL, R/R DLBLC ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies who failed or are ineligible for any standard therapies. Patients must have ECOG ≤2, and adequate organ function with prior treatment-related toxicities resolved to ≤ Grade 2. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective 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), time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels in the escalation phase and during the expansion cohort portion of the study. The first patient in the study is anticipated to dose in Q1 of 2022. Citation Format: Farhad Ravandi-Kashani, Ashwin Kishtagari, Hetty Carraway, Emily Curran, Gary Schiller, Alex Cacovean, Bhagyashree Yadav, Thomas Butler, Jeffrey Lancet. A phase 1 study of BMF-219, a novel oral irreversible menin inhibitor, as single-agent in patients with relapsed/refractory (R/R) acute leukemia (AL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT210.
Published Version
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