Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling.
BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL).
Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design.
Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted.
Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D.
Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1.
Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B).
BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure.
BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3).
The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment.
Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.
Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28.
Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.
Disclosures
Lancet:Atheneum: Consultancy; The Dedham Group: Consultancy; Tegus: Consultancy; AbbVie Inc.: Consultancy; BerGenBio / DAVA Oncology: Consultancy; Boxer Capital: Consultancy; Servier: Consultancy; Peer Voice: Consultancy; Celgene: Consultancy, Research Funding; Globe Life Sciences: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MD Anderson: Consultancy; MEDTalks: Consultancy; Novartis: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Biomea fusion: Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos:Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; GILEAD: Consultancy; OTSUKA: Consultancy; Novartis: Consultancy, Research Funding; INCYTE: Consultancy; NERVIANO: Consultancy; BEIGENE: Consultancy; Celgene: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Jazz pharma: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Ryvu: Consultancy; Kura oncology: Consultancy; Menarini-Stemline: Consultancy, Research Funding; Janssen: Speakers Bureau; BMS: Consultancy, Other, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Barrientos:AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Jannsen: Consultancy. Alegre:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bergua Burgues:Hospital San Pedro de Alcántara. Servicio de Hematologia. Cáceres. SPAIN: Current Employment; Fundesalud. Grants of Europena funds.Daychii: Research Funding; Daychii: Consultancy. Curran:Incyte: Other: Advisory board; Servier: Consultancy, Other: Expert consensus panel; Jazz: Other: Advisory board; Pfizer: Honoraria, Other: Advisory board; Kite: Other: Advisory board; Amgen: Other: Advisory board. de Leeuw:Takeda: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Servier: Consultancy. Derenzini:Incyte: Other: advisory board; ADC Therapeutics: Research Funding; TAKEDA: Other: advisory board, Research Funding; BEIGENE: Other: Advisory board; ASTRAZENECA: Other: Advisory Board; ROCHE: Other: advisory board, Speakers Bureau. Janssen:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Apps for Care and Science and non-profit foundation support ; Jazz: Other: Apps for Care and Science and non-profit foundation support ; Servier: Other: Apps for Care and Science and non-profit foundation support ; Sanofi Gemzyme: Other: Apps for Care and Science and non-profit foundation support ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Apps for Care and Science and non-profit foundation support ; Olympus: Other: Apps for Care and Science and non-profit foundation support ; Janssen: Other: Apps for Care and Science and non-profit foundation support ; Daiichi-Sankyo: Other: Apps for Care and Science and non-profit foundation support ; Astellas: Other: Apps for Care and Science and non-profit foundation support ; Amgen: Other: Apps for Care and Science and non-profit foundation support ; BMS: Other: Apps for Care and Science and non-profit foundation support , Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jongen-Lavrencic:Ellipses Pharma: Research Funding. Kishtagari:Servier Pharmaceuticals: Consultancy; Geron Corporation: Honoraria; CTI BioPharma Corp., a Sobi company: Consultancy, Honoraria, Speakers Bureau. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Regeneron: Honoraria. Morillo:GSK: Honoraria; ABBVIE: Honoraria. Rambaldi:Abbvie: Honoraria. Schiller:Delta-Fly Pharma: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Mateon Therapeutics: Research Funding; Pfizer: Research Funding; Precog: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Onconova Therapeutics: Research Funding; Trovagene: Research Funding; Fujifilm: Research Funding; FORMA Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Agios: Research Funding; ElevateBio: Research Funding; Tolero Pharmaceuticals: Research Funding; Takeda: Research Funding; Stemline Therapeutics: Research Funding; Sellas Life Sciences: Research Funding; Sangamo Bioscience: Research Funding; Samus Therapeutics: Research Funding; REGiMMUNE: Research Funding; Geron: Research Funding; Genentech/Roche: Research Funding; Gamida Cell: Research Funding; Actuate Therapeutics: Research Funding; Arog: Research Funding; Celator: Research Funding; Constellation Pharmaceuticals: Research Funding; Actinium Pharmaceuticals: Research Funding; Sanofi: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Kite: Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Agios: Consultancy; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Kronos Bio: Research Funding; Ono Pharmaceutical: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau. Ahmed:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Cacovean:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Iovance: Current equity holder in publicly-traded company. Morris:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Follit:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Munneke:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Waghmare:Biomea Fusion: Current Employment. Mandap:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Vimal:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company. Butler:Biomea Fusion: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Carraway:Celgene: Research Funding; Genentech: Consultancy; Astex Pharmaceuticals: Other; Novartis: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Stemline Therapeutics: Consultancy, Speakers Bureau; Takeda: Other; Daiichi: Consultancy; BMS: Consultancy, Research Funding, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; AbbVie: Other; Syndax: Other: DSMB.
