Phase 1b Study of Menin-KMT2A Inhibitor Bleximenib in Combination with Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with KMT2Ar or NPM1 Alterations

Background: Newly diagnosed (ND) acute myeloid leukemia (AML) is a genetically heterogeneous disease with a median 5-year overall survival of approximately 30%. Combining standard intensive chemotherapy (IC) approaches with targeted therapies may further improve outcomes. Bleximenib is a potent, selective menin-KMT2A complex inhibitor with activity in NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AML when given either as monotherapy or in combination for relapsed/refractory disease (Jabbour et al., ASH 2023; Wei et al., EHA 2024). The focus of this study has been to explore the safety and preliminary efficacy of combining bleximenib with IC for ND AML.

Aims: To determine the safety and preliminary efficacy of bleximenib in combination with intensive cytarabine + daunorubicin/idarubicin, followed by cytarabine consolidation for ND NPM1m or KMT2Ar AML participants (pts) eligible for IC.

Methods: NCT05453903 is an ongoing Phase 1b, multicenter, dose-finding study. In dose escalation, pts received a standard '7+3' regimen of cytarabine 200mg/m²/day and daunorubicin 60mg/m²/day IV or idarubicin 12mg/m²/day IV. Bleximenib was administered orally, twice daily (BID), and dosed continuously. Pts who achieved a complete remission (CR) received consolidation therapy with up to 4 cycles of intermediate-dose cytarabine plus bleximenib. Those not proceeding to allogeneic hematopoietic stem cell transplant could receive bleximenib continuation for up to 12 months. As of July 16^th 2024, bleximenib doses ≥30 mg BID have been explored in combination with '7+3' IC. The safety dataset includes all dosed pts, with adverse events (AEs) reported per CTCAE v5. The efficacy dataset, as assessed by investigators (per modified ELN 2017), comprises ND pts with NPM1m or KMT2Ar who received ≥50 mg bleximenib BID in combination with '7+3' IC and completed at least 1 disease evaluation.

Results: In the safety dataset, 22 ND AML pts (median age: 58 [27-70] years; 54.5% female, 45.5% male; 11 NPM1, 11 KMT2A altered) received bleximenib across dose levels explored in combination with IC. 95% (21/22) of pts had ≥1 treatment-emergent AE (TEAE, all grades): diarrhea (17/22; 77%), thrombocytopenia (15/22; 68%), febrile neutropenia (14/22; 64%), pyrexia (13/22; 59%), anemia and nausea (11/22; 50% each) were the most common. Grade ≥3 TEAEs also occurred in 95% (21/22) of pts; the most frequent events were febrile neutropenia (14/22; 64%), thrombocytopenia (15/22; 68%), anemia, neutropenia (9/22; 41% each) and leukopenia (6/22; 27%). TRAEs (all grades) attributed to bleximenib alone occurred in 18% (4/22) of pts, including thrombocytopenia and neutropenia (2/22; 9% each) and single cases (5% each) of anemia, diarrhea, cerebrovascular accident, dysesthesia and upper abdominal pain. Grade ≥3 TRAEs attributed to bleximenib alone occurred in 14% (3/22) of pts, including thrombocytopenia (2/22; 9%) and single cases (5% each) of anemia and neutropenia. No differentiation syndrome (DS) or dose-limiting toxicities (DLTs) were observed. Two episodes of Grade 1 QTcF prolongation were recorded but not attributed to bleximenib. In pts who achieved initial blast clearance, the median time from Day 1 of induction to platelet count recovery (50x10⁹/L) was 32 days (range, 22-45), and the median time to neutrophil count recovery (0.5x10⁹/L) was 32 days (range, 25-45). The efficacy dataset includes 14 pts (8 NPM1m, 6 KMT2Ar). In this population, overall response rate (ORR: ≥PR) was 93% (79% CR; 86% CR/CRh) and median time to CR was 30 days (range, 22-41). By genotype, the ORR was 83% in pts with KMT2Ar AML (83% CR/CRh) and 100% in pts with NPM1m (88% CR/CRh). Of those pts who have completed consolidation therapy, five have proceeded to allogeneic hematopoietic stem cell transplantation.

Summary/Conclusion: Dose escalation is ongoing in this Phase 1b study. Preliminary results demonstrate that bleximenib in combination with ‘7+3‘ IC regimen in ND AML pts eligible for such therapy has an acceptable safety profile with no DS or DLTs observed. There is no consistent delay in neutrophil or platelet count recovery after induction. In addition, preliminary antileukemic activity is observed in pts with ND NPM1m or KMT2Ar AML treated with bleximenib in combination with IC.

Recher:Abbvie, Astellas, BMS, Daiichi-Sankyo, Iqvia and Jazz Pharmaceuticals: Other: Research Funding to my institution. O'Nions:Jazz: Honoraria; Servier: Honoraria; Janssen/Johnson and Johnson: Honoraria; Astellas: Other: Speakers fees; Abbvie: Honoraria. Aldoss:Sobi: Other: consulting fees; Pfizer: Honoraria, Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees; Jazz Pharmaceuticals: Other: consulting fees; Takeda Pharmaceuticals: Other: consulting fees; Kite Pharma: Other: consulting fees; AbbVie: Other: research support; Amgen: Honoraria, Other: consulting fees. Pierola:AstraZeneca: Research Funding; Astellas, BMS, Jazz Pharma, Syros: Consultancy; Abbvie, BMS, Jazz Pharma, Novartis, Syros: Speakers Bureau. Allred:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Barreyro:Janssen R&D: Current Employment; Johnson & Johnson: Current equity holder in publicly-traded company. Curtis:Johnson & Johnson: Current Employment. Daskalakis:Janssen: Current Employment, Current equity holder in private company; Sanofi: Current equity holder in private company. Della Porta:Bristol Myers Squibb: Consultancy. Döhner:Abbvie: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Astra Zeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Stemline: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Astellas: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Kronos Bio: Research Funding. D'Souza:Johnson & Johnson: Current Employment. Exum:Janssen: Current Employment, Current equity holder in publicly-traded company. Fathi:Novartis: Consultancy; EnClear: Consultancy; Servier: Consultancy, Research Funding; ImmunoGen: Consultancy; Mablytics: Consultancy; Ipsen: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Forma: Consultancy; PureTech: Consultancy; Abbvie: Consultancy, Research Funding; Astellas: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; BMS/Celgene: Consultancy; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; MorphoSys: Consultancy; Kite: Consultancy; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria; Agios: Ended employment in the past 24 months; Amgen: Consultancy; Orum: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Menarini Group: Consultancy; Remix: Consultancy; Ispen: Consultancy; Autolus: Consultancy; AstraZeneca: Honoraria; Genentech: Honoraria; Rigel: Consultancy. Fedele:BMS: Research Funding; Amgen, Pfizer, Adaptive Biosciences: Membership on an entity's Board of Directors or advisory committees. Ferrante:Johnson & Johnson: Current Employment. Gaj:Janssen R&D (Johnson & Johnson): Current Employment. Garciaz:Janssen: Consultancy, Honoraria; Imcheck Therapeutics: Consultancy; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Other: travel grant; Abbvie: Consultancy, Honoraria, Other: Travel grant; BMS: Consultancy. Garrido Paniagua:BMS: Other: travel grants; Novartis: Honoraria, Other: Educational programs and travel grants. Guttke:Johnson & Johnson Innovative Medicine: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Gyan:BMS: Honoraria, Research Funding; Sandoz: Research Funding; Astra Zeneca: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Kephren Publishing: Honoraria; Recordati: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Axonal: Honoraria; Servier: Honoraria; Gilead Kite: Honoraria. Hiebert:Johnson & Johnson: Other: Functional Service Provider (FSP) from IQVIA . Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Jentzsch:Jazz Pharmaceuticals: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Delbert Laboratories: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Konopleva:Legend Biotech: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharmaceutical: Research Funding; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Other: Clinical Trials; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Other: clinical trials; Boehringer: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; ImmunoGen: Research Funding; Allogene: Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sellas: Consultancy; Pfizer: Other: clinical trials; Reata Pharmaceutical: Other: IP; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Redona: Consultancy; Precision Biosciences: Research Funding; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding. Krönke:Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Speakers Bureau; Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Honoraria; Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Consultancy; Charité - Universitätsmedizin Berlin: Current Employment. Kwon:Janssen Pharmaceutica: Current Employment. Loefgren:Johnson & Johnson: Current Employment. Lomas:Johnson & Johnson: Current Employment. Mancini:ASST Grande ospedale Metropolitano Niguarda - Public Hospital: Current Employment. Martinelli:Bristol Myers Squibb (BMS): Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Research Funding. Morillo Giles:Roche, TAKEDA, GSK: Honoraria. Murphy:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Packman:Janssen: Current Employment, Current equity holder in publicly-traded company. Papayannidis:Blueprint: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Amgen: Honoraria; BMS: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; Menarini/Stemline: Honoraria. Philippar:Johnson&Johnson Innovative Medicine: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Salamero:Astellas, Jazz, BMS: Consultancy; Jazz, Abbvie: Honoraria. Sanga:Alcon Laboratories, inc: Current equity holder in publicly-traded company; Janssen: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sauer:Abbvie: Other: financial support . Searle:Incyte: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; DarkBlue Therapeutics: 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; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Beigene: Honoraria; Nurix: Honoraria; Jazz: Speakers Bureau. Tucker:Viridian Therapeutics: Current equity holder in publicly-traded company; Guardant Health: Current equity holder in publicly-traded company; Kura Oncology: Current equity holder in publicly-traded company; Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company; Cullinan Oncology: Current equity holder in publicly-traded company; Voyager Therapeutics: Current equity holder in publicly-traded company; Tracon Pharmaceuticals: Current equity holder in publicly-traded company; Erasca INC: Current equity holder in publicly-traded company; Bellicum Pharmaceuticals: Current equity holder in publicly-traded company; G1 Therapeutics: Current equity holder in publicly-traded company. Vyas:Abbvie, Servier, Rigel, Syndax, AstraZeneca, Debiopharm, Charm Therapeutics: Consultancy; Yellowstone Biosciences: Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Auron Therapeutics: Membership on an entity's Board of Directors or advisory committees. Wei:Novartis, Astellas, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, Macrogenics and Agios.: Membership on an entity's Board of Directors or advisory committees; AbbVie, Novartis, BMS and Astellas: Speakers Bureau; Novartis, AbbVie, Servier, BMS, Syndax, Astex, AstraZeneca and Amgen: Research Funding; Walter and Eliza Hall Institute (WEHI): Current Employment, Other: eligible for financial benefits associated with payments which the WEHI receives in relation to venetoclax.