Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustaining leukemic cells with KMT2A and NPM1 alterations (Kuhn 2016). JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A with preclinical activity in KMT2A-rearranged or NPM1-mutated leukemic cell lines and primary leukemia patient samples in vitro and in vivo (Kwon 2022). We report initial data investigating JNJ-75276617 in adult participants (pts) with R/R acute leukemia harboring KMT2A alterations (rearrangements, amplifications, or partial tandem duplications) or NPM1 mutations.

Methods: 75276617ALE1001 (NCT04811560) is an ongoing Phase 1, multicenter, open-label, dose-finding study. Pts in dose escalation receive JNJ-75276617 orally on a 28-day cycle. As of 8 April 2023, multiple dose levels ≥15 mg have been explored on either a daily or twice daily (BID) dosing schedule. AEs were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2017. Preliminary safety, efficacy and PD data are reported herein, with a focused review of the efficacy in higher dose levels with ≥3 pts dosed.

Results: Fifty-eight pts received JNJ-75276617. The median age was 63 (range: 19-83) years; 56 pts (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (range: 1-7), including 10 (17%) pts with a prior allogeneic stem cell transplant. A KMT2A or NPM1 alteration was present in 33 (57%) and 25 (43%) pts, respectively.

Thirty (52%) pts experienced ≥1 treatment-related AE (TRAE); most commonly differentiation syndrome (DS) (8 [14%]). Grade ≥3 TRAEs were observed in 17 (29%) pts; those reported in ≥2 pts were neutropenia (6 [10%]), anemia and thrombocytopenia (4 [7%] each), DS (3 [5%]), and ALT and AST increase (2 [3%] each). Dose limiting toxicities (DLTs) were observed in 5 (9%) pts, with DS (2 [3%]) as the only DLT reported in ≥2 pts.

In 26 (63%) of the 41 pts with disease evaluation data, there was a reduction in bone marrow (BM) disease burden ( Figure 1). Of these, a ≥50% decrease in BM blasts was observed in 16 (39%) pts. In the highest dose level with ≥3 pts (90 mg BID; n=8), the ORR (≥PR) was 50% (n=4), with all responders ongoing ( Figure 2). These responders (2 NPM1-, 2 KMT2A-altered) achieved CR (1 pt), CRh (1 pt), and CRi (2 pts). In a review of higher dose levels with ≥3 pts (≥45 mg BID; n=20), the ORR was 40% (n=8), with 7 responders ongoing ( Figure 2). These responders (5 NPM1-, 3 KMT2A-altered) achieved CR (3 pts), CRh (1 pt), CRi (3 pts), and PR (1 pt); median (range) time to first response (≥PR) 1.81 mos (1.0-3.3; n=8); time to CR, CRh, or CRi 1.77 mos (1.0-3.3; n=7); and time to CR 2.79 mos (1.8-2.9; n=3). Across all cohorts there were 12 responders, including 1 MRD negative CR. One responder discontinued treatment for allogeneic transplant; however, 8 responders continue on treatment, including 2 pts in cycle 9.

Preliminary PD data from unfractionated BM and/or PBMCs in paired samples among responders (n=12) show biologic activity as indicated by reduction in expression (mean fold change from baseline calculated as [on-tx-baseline]/baseline [range]) of menin-KMT2A target genes ( MEIS1 -0.42 [-1.0-9.0]; HOXA9 -0.03 [-1.0-21.7]; FLT3 18.6 [-1.0-425]) and induction of genes associated with differentiation ( ITGAM 55.0 [-0.93-1467]; MNDA 5.9 [-1.0-83.5]). Compared to baseline, the percentage of KMT2A-altered cells or NPM1 variant allele frequency (VAF) was reduced in responders, with a decrease in KMT2A-altered cells by break-apart FISH probe from 59.2% at baseline to 8.1% post-treatment and in NPM1 VAF using a myeloid gene NGS panel from 13.1% at baseline to 2.8% post-treatment.

Conclusions: Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations.

Jabbour:Adaptive Biotech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Searle:Sanofi: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Other: Conference travel; Janssen: Honoraria, Other: Conference travel. Abdul-Hay:Jazz: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Servier: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Abedin:AbbVie: Consultancy, Honoraria; Actinium Pharmaceutical: Research Funding; AltruBio: Research Funding; Incyte: Research Funding; Daichii Sankyo: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Aldoss:Sobi: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy; KiTE: Consultancy. Alfonso Piérola:Syros: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Astra Zeneca: Research Funding; Astellas: Consultancy. Alonso-Dominguez:Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding; Pfizer: Research Funding. Chevallier:Mallinckrodt Pharmaceuticals: Honoraria; Sanofi: Honoraria; Incyte: Honoraria, Research Funding; Takeda: Honoraria; Immedica Pharma: Honoraria; Servier: Honoraria. Cost:Janssen: Current Employment. Daskalakis:Janssen: Current Employment, Current holder of stock options in a privately-held company; Sanofi: Current holder of stock options in a privately-held company. Dillon:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AvenCell: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; Shattuck labs: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Esteve:Pfizer: Research Funding; Gilead: Consultancy; Astellas: Consultancy; Kronos Bio: Research Funding; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Fathi:Forma: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Autolus: Consultancy; Enclear: Consultancy; Genentech: Consultancy; Immunogen: Consultancy; Celgene: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Takeda: Consultancy; Mablytics: Consultancy; Kite: Consultancy; Ipsen: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy; Menarini: Consultancy; Rigel: Consultancy; Novartis: Consultancy; Remix: Consultancy; Orum: Consultancy; Pfizer: Consultancy; PureTech: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amgen: Consultancy. Fedele:Pfizer: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Research Funding. Ferrante:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Guttke:Janssen R&D: Current Employment, Current equity holder in publicly-traded company. Gyan:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Fresenius Kabi: Research Funding; Gilead: Honoraria; Roche: Honoraria; Alexion: Honoraria; Chugai Pharma: Research Funding; Astra Zeneca: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Recordati: Consultancy. Kwon:Janssen Pharmaceutica: Current Employment. Miller:Janssen: Current Employment. Packman:Janssen: Current Employment, Current equity holder in publicly-traded company. Philippar:Janssen: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Pigneux:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: 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, Other: Support for attending meetings; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Recher:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharamceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Iqvia: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salamero:Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Sanga:Janssen: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Alcon Laboratories, Inc.: Current equity holder in publicly-traded company. Stone:Epizyme: Other: DSMB; Aptevo: Other: DSMB; CTI Biopharma: Consultancy; GSK: Consultancy; Kura One: Consultancy; BerGenBio: Consultancy; Syntrix: Other: DSMB; Rigel: Consultancy; Jazz: Consultancy; Cellularity: Consultancy; Lava Therapeutics: Consultancy; Hermavant: Consultancy; Ligand Pharma: Consultancy; Takeda: Other: DSMB; AvenCell: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Tan:Genor Biopharma Co. Ltd: Research Funding; Qilu Pharmaceuticals Co. Ltd: Research Funding; Shanghai EpimAb Biotherapeutics: Research Funding; Kartos Therapeutics: Research Funding; Loxo Oncology at Lilly: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Ellipses Pharma: Research Funding; Beigene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Constellation Pharmaceuticals, Inc: Research Funding; Protagonist Therapeutics, Inc: Research Funding; Ichnos Sciences SA: Research Funding; Bristol-Myers Squibb: Research Funding. Thuring:Janssen: Current Employment, Current equity holder in publicly-traded company. Tucker:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company; Kura Oncology: Current equity holder in publicly-traded company; Guardant Health: Current equity holder in publicly-traded company; Viridian Therapeutics: 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:Pfizer: Honoraria; Gilead: Honoraria; BMS: Research Funding; Auron Therapeutics: Current holder of stock options in a privately-held company; Astellas: Honoraria; Jazz: Honoraria; Abbvie: Consultancy, Honoraria.

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2023
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