Background: Patients (Pts) with NPM1-mutated/FLT3-ITD wild type (NPM1+/FLT3-ITD-) AML are a subset that benefit from intensive chemotherapy (Ara-C+DNR [7+3]/Ara-C consolidation). Spleen tyrosine kinase (SYK) is a recently identified target in AML. Emerging results from clinical studies of ENTO, a potent and selective oral SYK inhibitor, in combination with 7+3 in AML have been promising. Herein, we report the results of a Phase 2 sub-study of the Beat AML Master Trial that assessed the efficacy of ENTO with 7+3 induction(IND) and ENTO+Ara-C consolidation(CON) therapy in ND adult NPM1+/FLT3-ITD- AML pts [ClinicalTrials.gov: NCT03013998]

Methods: This multicenter (17 sites), open-label, Phase 2 combination study utilized Simon's 2-stage Phase 2 design and enrolled AML pts that were NPM1+/FLT3-ITD- identified by the LabPMM FLT3 and NPM1 assays and/or the Foundation Medicine HemeOne panel. Pts were eligible if aged ≥18 years and had ECOG performance status 0-2. Pts received ENTO 400 mg orally twice-daily for 28 days, starting Day 1 of IND and CON cycles. Ara-C was dosed 100 mg/m2/day IV over 24 hours on days 1-7 during IND cycle. DNR was dosed 60 mg/m2/day IV on days 1-3 during IND. During CON ,depending on age, Ara-C was given 1 or 3 g/m2 IV Q12 on days 1, 3, and 5 of each cycle. Nine pts initially received 5 days of ENTO lead-in (later discontinued after protocol amendment ). Pts started induction (IND) with ENTO and 7+3 dosed concurrently for up to 2 cycles. Pts who achieved CR/CRh/CRi during IND proceeded to consolidation (CON) and were treated with ENTO + Ara-C for up to 4 cycles. Pts who did not achieve CR/CRh/CRi after IND came off study. After completion of CON, study treatment was completed and pts went into the follow up phase of the study. Transplant was allowed at any point during the study. MRD was measured using the LabPMM NPM1 assay with a sensitivity of 5X10-5 mutant alleles/total alleles.

Response was assessed using modified 2017 ELN AML criteria. The primary endpoint was composite complete remission (CCR) rate (CR+CRh+CRi) after IND. The null hypothesis, based on published data from Alliance studies of 7+3 regimens in this specific population, estimated a CR/CRh/CRi rate of 65% vs the alternative of 85% (one-sided α=0.025, power 88%). Utilizing a Simon 2 stage design, Stage 1 required greater than or equal to 14 responses in order to proceed to Stage 2.

Results: Between Oct 2017 and Dec 2021, of the 30 pts enrolled, 27 pts with confirmed eligibility are included in the analyses. Median age was 66 years (range: 32-75) (Table 1). Median time on Tx was 129 days (range: 12-613). CCR rate with up to 2 cycles of IND Tx was 20/27 (74%); with CR of 18/27 or 67% (3 CRMRD-, 5 CRDMRD+, and 10 CRMRDUNK), CRh and CRi (1/27 or 4% each) (Table 2). Overall CR+CRh+CRi rate was 78%. Median duration of response was 15.7 months. Most common reasons for study discontinuation were adverse events (AEs; 22%) and PD/recurrence/relapse after response (19%). Two pts (7%) proceeded to transplant. After a median follow-up of 16.3 months, 62% of pts were 1-year disease-free and median OS (mOS) was 40.3 months. Deaths within 30- and 60-days of treatment were 1 and 1 pts, respectively.

The most common adverse events (AEs; any grade) were nausea (70%), diarrhea (67%), and febrile neutropenia (59%). Overall, 21 pts reported 204 Tx-related Grade ≥3 AEs. The most common Tx-related Grade ≥3 AEs were febrile neutropenia (48%), sepsis and maculo-papular rash (7% each). Thirteen pts had 27 serious AEs (SAEs), and 8 pts had 14 Tx-related SAEs. Most common Tx-related and Grade ≥3 SAEs were febrile neutropenia and sepsis (7% each). Two pts had SAEs that led to death (1 intracranial hemorrhage and 1 cerebrovascular accident). The most common Grade ≥3 clinical laboratory abnormalities were thrombocytopenia (33%), neutropenia (30%), and anemia and leukopenia (26% each). The most common ENTO-related AEs (any grade) were hyperbilirubinemia (44%), nausea (30%) and diarrhea (22%).

Conclusions: ENTO with 7+3 IND and Ara-C CON therapy demonstrated a high CCR rate and encouraging mOS in ND NPM1+/FLT3-ITD- AML pts up to age 75. Stage 1 of the study was positive, allowing enrollment into Stage 2 however Stage 2 of this study is not currently being pursued to prioritize enrollment onto the global registrational Phase 3 double-blind study of ENTO in Combination With Intensive Induction and Consolidation Chemotherapy (NCT05020665) assessing MRD negative CR in NPM1+ AML pts.

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Borate:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Huang:AstraZeneca: Other: Statistical support. Stein:PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Auron Therapeutics: Current equity holder in private company; Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy. Foran:AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding; Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities. Baer:AbbVie: Research Funding; Ascentage: Research Funding; Kura Oncology: Research Funding; Kite, a Gilead Company: Research Funding; Takeda: Research Funding; Forma: Research Funding. Stock:MorphoSys: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pluristem: Consultancy, Honoraria; Amgen: Honoraria; Agios: Honoraria; Kura Oncology: Honoraria; Kite: Honoraria; Jazz Pharmaceuticals: Honoraria; Servier: Honoraria; Newave Pharmaceuticals: Consultancy; Syndax: Consultancy, Honoraria. Odenike:Abbvie; Impact Biomedicines; Celgene; Novartis; BMS; Taiho Pharmaceutical; CTI; Threadwell therapeutics; Bristol-Myers Squibb/Celgene (Inst): Consultancy; Celgene (Inst); Incyte (Inst); Astex Pharmaceuticals (Inst); NS Pharma (Inst); Abbvie (Inst); Janssen Oncology (Inst); OncoTherapy Science (Inst); Agios (Inst); AstraZeneca (Inst); CTI BioPharma Corp (Inst); Kartos Therapeutics (Inst); Aprea AB (Inst): Research Funding. 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Smith:Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Erasca: Research Funding; Revolution Medicines: Research Funding. Olin:Cellectis: Other: NA; Actinium: Consultancy; Astellas: Consultancy; Abbvie: Consultancy. Arellano:Syndax Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Schiller:Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Regimmune: Research Funding; Jazz: Consultancy; Cellerant: Research Funding; Sellas: Research Funding; AltruBio: Research Funding; Arog: Research Funding; Stemline: Speakers Bureau; Kite, a Gilead Company: Research Funding, Speakers Bureau; Glycomimetics: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; AVM Biopharma: Research Funding; Samus: Research Funding; Actinium: Research Funding; AbbVie: Research Funding, Speakers Bureau; Ono Pharma: Honoraria; Cyclacel: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; PreCOG LLC: Research Funding; Gilead: Research Funding; Cellectis: Research Funding; Trovagen: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Actuate: Research Funding; Genentech-Roche: Research Funding; Deltafly: Research Funding; Forma: Research Funding; Astellas: Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria; Geron: Research Funding; CTI: Research Funding; Constellation: Research Funding; Novartis: Honoraria, Other: Speaker fees, Research Funding; AstraZeneca: Honoraria; Johnson & Johnson: Current equity holder in publicly-traded company; Stemline: Research Funding; Mateon: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Karyopharm: Research Funding, Speakers Bureau; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Deciphera: Research Funding; Medimmune: Research Funding; Onconova: Research Funding; Sangamo: Research Funding; Takeda: Research Funding; Tolero: Research Funding. Lin:AbbVie, Aptevo, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Mateon Therapeutics, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Foster:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Research Funding; Macrogenics: Research Funding; Newave Pharmaceuticals: Research Funding; Rafael Pharmaceuticals: Research Funding; Zentalis Pharmaceuticals: Consultancy; Bellicum Pharmaceuticals: Research Funding. Boyiadzis:Genentech: Current Employment. Redner:Pfizer: Current equity holder in publicly-traded company. Curran:Amgen: Consultancy, Other: Participation in advisory board; Incyte: Consultancy, Other: Participation in advisory board; Kite: Consultancy, Other: Participation in advisory board; Pfizer: Consultancy, Other: Participation in advisory board; Tempus: Consultancy, Other: Participation in advisory board; Servier: Consultancy, Honoraria, Other: Participation in advisory board; participation in expert panel guidelines. Levine:Imago, Mission Bio, Bakx, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ajax, Abbvie, Constellation, Zenalis, Celgene, Roche, and Prelude: Other: research support; Qiagen: Other: supervisory board member; Astra Zeneca and Kura: Other: honoraria for invited lectures ; Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis: Consultancy; Gilead and Novartis: Other: Grant reviews. Druker:US Patent: Patents & Royalties: 11049247; (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license, one CytoImage, Inc. exclusive license, and one Sun Pharma Advanced Research Company non-exclusive license): Patents & Royalties: Patent 6958335; Sun Pharma Advanced Research Company: Patents & Royalties: Mutated ABL Kinase Domains (non-exclusive license); CytoImage: Patents & Royalties: QD Molecular Assay for Personalized Oncoprotein Detection in Leukemia (exclusive license); US Patent: Patents & Royalties: 10664967; US Patent: Patents & Royalties: 7592142; US Patent: Patents & Royalties: 6958335; US Patent: Patents & Royalties: 10473667; US Patent: Patents & Royalties: 7416873; Merck: Patents & Royalties: Monoclonal antiphosphotyrosine antibody 4G10; US Patent: Patents & Royalties: 4326534; Astra-Zeneca: Other: Clinical Trial Funding, Research Funding; Recludix Pharma: Other: Sponsored Research Agreement ; Enliven Therapeutics: Other: Sponsored Research Agreement ; VB Therapeutics: Other: Founder; Multicancer Early Detection Consortium: Membership on an entity's Board of Directors or advisory committees; Beat AML LLS: Other: Joint Steering Committee ; CureOne: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Recludix Pharma: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; GRAIL: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Iterion Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Enliven Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Blueprint Medicines: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Aptose Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; RUNX1 Research Program: Other: Scientific Advisory Board ; Novartis: Other: Scientific Advisory Board; Clinical Trial Funding , Patents & Royalties: 6958335 (exclusive license), Research Funding; Nemucore Medical Innovations: Other: Scientific Advisory Board ; DNA SEQ: Other: Scientific Advisory Board ; Celgene: Other: Scientific Advisory Board ; Cepheid: Other: Scientific Advisory Board ; Therapy Architects (ALLCRON): Other: Scientific Advisory Board ; Aileron Therapeutics: Other: Scientific Advisory Board ; Adela Bio: Other: Scientific Advisory Board . Byrd:TG Therapeutics: Honoraria; AstraZeneca: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Syndax: Consultancy; Pharmacyclics LLC: Honoraria, Research Funding; Kura Oncology, Inc: Consultancy; Novartis: Consultancy, Honoraria; Vincerx Pharma: Current equity holder in publicly-traded company; Xencor, Inc: Research Funding. Mims:Syndax: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Ryvu: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Other: Data Safety and Monitoring Board; Jazz Pharmaceuticals: Other: Data Safety and Monitoring Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

Author notes

*

Asterisk with author names denotes non-ASH members.

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2022
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