Rp2d Determination of Bleximenib in Combination With Ven+aza: Phase 1b Study in Nd & R/r Aml With Kmt2a Type: Oral Presentation Andrew H. Wei Kmt2a/npm1 Npm1alterations
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Background Bleximenib (blex) is a potent, selective menin inhibitor with activity in NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML). Monotherapy activity for relapsed/refractory (R/R) AML was established at a recommended Phase 2 dose (RP2D) of blex 100 mg twice daily (BID) with a 50 mg BID step-up dose (NCT04811560). We report evaluation of updated data determining the RP2D for blex in combination with VEN+AZA in participants (pts) with R/R AML or newly diagnosed (ND) AML who are unfit for intensive chemotherapy. Methods NCT05453903 is an ongoing Phase 1b dose-finding study in which pts receive VEN+AZA in combination with oral blex BID at 15–150 mg (R/R) or 30–100 mg (ND) over a 28-day cycle and during count recovery. Bleximenib was started at day +4 without the need for step-up dosing. Safety analysis includes all dosed pts. Intention to treat efficacy analysis includes NPM1m or KMT2Ar AML pts receiving 50 mg, 100 mg or 150 mg blex BID in combination with VEN+AZA, including pts who discontinued prior to first disease evaluation. Each pt provided informed consent. Results As of February 2025, 120 pts received blex with VEN+AZA (R/R, n = 86; ND, n = 34) Median age was 66.5 years (range: 19–88), 52 had KMT2A and 68 NPM1m. R/R pts received 1 (36%) or 2 (42%) lines of prior treatment; 46.5% had prior VEN. In the safety analysis (N = 120) the most common all-grade (G) treatment-emergent adverse events (TEAEs) were nausea (60%), thrombocytopenia (55%) and anemia (51%) The most common ≥ G3 TEAEs were thrombocytopenia (53%) anemia (48%) and neutropenia (46%) 5 events of differentiation syndrome (DS; 4%) were observed: 4 G2–3; 1 G5 (in a pt with adverse karyotype and progressive disease) which met dose-limiting toxicity (DLT) criteria. A DLT of G3 diverticulitis was also reported. No QT prolongation related to study treatment has been reported to date. Safety profiles were comparable among dose groups, disease subtypes and settings. Pharmacodynamic (PD) data demonstrated robust reduction in target gene expression, with a more rapid reduction in NPM1 mutational burden and elimination of CD11b+ blasts in the blex 100 mg BID vs blex 50 mg BID cohort. In the R/R efficacy dataset (blex BID 50 mg n = 26; 100 mg, n = 24; 150 mg, n = 8) overall response (ORR) and composite complete response rates (cCR), regardless of genetic alteration, were lower with 50 mg (76% and 32%) vs 100 mg blex BID (79% and 54%) with no further improvement in efficacy observed at 150 mg BID. In ND pts (blex BID 50 mg, n = 13; 100 mg, n=13), ORR and cCR were also lower with blex 50 mg (77% and 62%) vs 100 mg BID (92% and 85%); data continue to mature. In ND and RR settings, there were no observed differences in response rates between KMT2Ar and NPM1m. Conclusion Evaluation of safety, efficacy, and tolerability data informed blex 100 mg BID as RP2D in combination with VEN+AZA for both R/R and ND pts with KMT2Ar or NPM1m AML. Bleximenib in combination with VEN+AZA has an acceptable safety profile, with no QTc prolongation signal observed to date. A blex 100 mg BID dose in combination with VEN+AZA resulted in optimal PD effects and improved depth of response, consistent with established monotherapy RP2D. The combinability of blex with VEN+AZA and promising efficacy support further exploration for KMT2Ar and NPM1m ND AML in the Phase 3 cAMeLot-2 study.
Authors: Andrew WEIL, Jordi ESTEVE REYNER, Sylvain GARCIAZ, Ibrahim ALDOSS, Alicia ALLRED, Juan Manuel ALONSO DOMINGUEZ, Laura BARREYRO, Pierre BORIES, Nikki DASKALAKIS, Matteo Giovanni DELLA PORTA, Hartmut DOHNER, Amber D'SOUZA, Amir FATHI, Pasquale FEDELE, Lucille FERRANTE, Rachel KOBOS, Stan GAJ, Ana GARRIDO DIAZ, Christina GUTTKE, Emmanuel GYAN, Brett HIEBERT, Elias JABBOUR, Danielle TRANCUCCI, Tosin BAMIDELE, Madlen JENTZSCH, Hagop KARNTARJIAN, Marina KONOPLEVA, Jan KRONKE, Marie Luise HÜTTER-KRÖNKE, Christina LOEFGRE, Oliver LOMAS, Valentina MANCINI, Ioannis MANTZARIS, Daniel MORILLO, Jenny O'NIONS, Kathryn PACKMAN, Cristina PAPAYANNIDIS, Christian RéCHER, Christoph ROELLIG, Olga SALAMERO, Prathap NAGARAJAHASTRI, Tim SAUER, Emma SEARLE, Natalia TOVAR, Nicolas VALLET, Lachlin VAUGHAN, Gala VEGA, Paresh VYAS, Uwe PLATZBECKER, Monserrat ROJAS
Institutions: Peter MacCallum Cancer Centre, Aix-Marseille Université, City Of Hope National Medical Center, City of Hope, Johnson & Johnson (United States), Institut universitaire du cancer de Toulouse Oncopole, IRCCS Humanitas Research Hospital, Harvard University, Monash Health, Monash University, Hospital de Sant Pau, Université de Tours, The University of Texas MD Anderson Cancer Center, Leipzig University, Charité – Universitätsmedizin Berlin, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Albert Einstein College of Medicine, Hospital Universitario Fundación Jiménez Díaz, University College London Hospitals NHS Foundation Trust, University College London, Hospital Clínic de Barcelona
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funder: Johnson and Johnson
OpenAlex ID: W7223118011