| Popis: |
Background: BMF-219 is a selective covalent inhibitor of menin, a transcriptional regulator of oncogenic signaling pathways in multiple cancers, that inhibits the menin/MYC interaction and downregulates the expression of MYC and MYC target genes, including KRAS. Mechanism of Action (hypothesis): In addition to MYC disruption, inhibition of the Menin-MLL complex by BMF-219 alters JunD genomic function, a crucial factor for KRAS-driven tumorigenesis. Inhibition of the Menin-MLL complex suppresses expression of Rasgrf1, which is essential for generation of the active RAS-GTP conformation of KRAS, activation of downstream pathways, and tumorigenesis. Preclinically, BMF-219 shows sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 exerts pan-mutant KRAS anticancer activity that is independent of the specific KRAS-activating mutation. Methods: COVALENT-102 (NCT05631574) is a prospective, open-label, multicenter, dose finding study evaluating the safety, tolerability, and clinical activity of escalating doses of BMF-219 administered daily in patients with unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2) & CRC (Cohort 3) with activating KRAS mutations who have received standard therapy. All indications as a group will follow a 3+3 dose escalation design. BMF-219 will be administered orally daily as continuous therapy as 28-days treatment cycle until progression or intolerability/unacceptable toxicity. Following conclusion of the dose-escalation, each indication will enroll patients in expansion cohorts independently to obtain further safety and efficacy data. Eligible patients include those with any KRAS mutation & (Cohort 1) stage IIIB/IV NSCLC with 2-4 prior lines of therapy including immune checkpoint inhibitors (ICI) &/or platinum-based chemo ± bevacizumab with ECOG PS 0-2; (Cohort 2) stage III/IV PDAC with ≥ 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel, ECOG PS 0-1; or (Cohort 3) stage III/IV CRC with ≥ 1 prior line of therapy including FOLFOX or FOLFIRI ± bevacizumab (prior ICI if MSI-H/dMMR), ECOG PS 0-2. Patients must have documented progression & measurable disease as defined by RECIST 1.1. Patients with prior KRAS inhibitor exposure are eligible. Key exclusion criteria include symptomatic &/untreated CNS metastasis, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine the optimal biological dose (OBD)/recommended Phase 2 dose (RP2D) of BMF-219 monotherapy. Secondary objectives include further evaluation of safety & tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and efficacy based on duration of response (DOR) & disease control rate (DCR). Assessment of progression-free survival (PFS), overall survival (OS) & time to response (TTR) are part of the exploratory endpoints. The first patient in the study is anticipated to be dosed in Q4 of 2022. Citation Format: Stacey A. Cohen, Christos Fountzilas, David Sommerhalder, Sandip Patel, Ai Benson, Kai He, Apar Ganti, Alex Spira, Bhagyashree (Kelshikar) Yadav, Alex Cacovean, Steve Morris, Tom Butler, David Hong. COVALENT-102: A phase 1/1b dose finding study of BMF-219, an oral covalent menin inhibitor, in patients with metastatic non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), and colorectal cancer (CRC) with activating KRAS mutations [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A003. |
