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

@article{weil2026rp2d,
  title = {{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}},
  author = {Andrew WEIL and Jordi ESTEVE REYNER and Sylvain GARCIAZ and Ibrahim ALDOSS and Alicia ALLRED and Juan Manuel ALONSO DOMINGUEZ and Laura BARREYRO and Pierre BORIES and Nikki DASKALAKIS and Matteo Giovanni DELLA PORTA and Hartmut DOHNER and Amber D'SOUZA and Amir FATHI and Pasquale FEDELE and Lucille FERRANTE and Rachel KOBOS and Stan GAJ and Ana GARRIDO DIAZ and Christina GUTTKE and Emmanuel GYAN and Brett HIEBERT and Elias JABBOUR and Danielle TRANCUCCI and Tosin BAMIDELE and Madlen JENTZSCH and Hagop KARNTARJIAN and Marina KONOPLEVA and Jan KRONKE and Marie Luise HÜTTER-KRÖNKE and Christina LOEFGRE and Oliver LOMAS and Valentina MANCINI and Ioannis MANTZARIS and Daniel MORILLO and Jenny O'NIONS and Kathryn PACKMAN and Cristina PAPAYANNIDIS and Christian RéCHER and Christoph ROELLIG and Olga SALAMERO and Prathap NAGARAJAHASTRI and Tim SAUER and Emma SEARLE and Natalia TOVAR and Nicolas VALLET and Lachlin VAUGHAN and Gala VEGA and Paresh VYAS and Uwe PLATZBECKER and Monserrat ROJAS},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.107930},
  url = {https://doi.org/10.1016/j.htct.2026.107930},
  note = {CC BY},
}

TY  - JOUR
TI  - 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
AU  - Andrew WEIL
AU  - Jordi ESTEVE REYNER
AU  - Sylvain GARCIAZ
AU  - Ibrahim ALDOSS
AU  - Alicia ALLRED
AU  - Juan Manuel ALONSO DOMINGUEZ
AU  - Laura BARREYRO
AU  - Pierre BORIES
AU  - Nikki DASKALAKIS
AU  - Matteo Giovanni DELLA PORTA
AU  - Hartmut DOHNER
AU  - Amber D'SOUZA
AU  - Amir FATHI
AU  - Pasquale FEDELE
AU  - Lucille FERRANTE
AU  - Rachel KOBOS
AU  - Stan GAJ
AU  - Ana GARRIDO DIAZ
AU  - Christina GUTTKE
AU  - Emmanuel GYAN
AU  - Brett HIEBERT
AU  - Elias JABBOUR
AU  - Danielle TRANCUCCI
AU  - Tosin BAMIDELE
AU  - Madlen JENTZSCH
AU  - Hagop KARNTARJIAN
AU  - Marina KONOPLEVA
AU  - Jan KRONKE
AU  - Marie Luise HÜTTER-KRÖNKE
AU  - Christina LOEFGRE
AU  - Oliver LOMAS
AU  - Valentina MANCINI
AU  - Ioannis MANTZARIS
AU  - Daniel MORILLO
AU  - Jenny O'NIONS
AU  - Kathryn PACKMAN
AU  - Cristina PAPAYANNIDIS
AU  - Christian RéCHER
AU  - Christoph ROELLIG
AU  - Olga SALAMERO
AU  - Prathap NAGARAJAHASTRI
AU  - Tim SAUER
AU  - Emma SEARLE
AU  - Natalia TOVAR
AU  - Nicolas VALLET
AU  - Lachlin VAUGHAN
AU  - Gala VEGA
AU  - Paresh VYAS
AU  - Uwe PLATZBECKER
AU  - Monserrat ROJAS
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.107930
UR  - https://doi.org/10.1016/j.htct.2026.107930
AB  - 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.
SN  - 2531-1379
SN  - 2531-1387
ER  -