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-Asterisk * with author name denotes a Non-ASH member
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2759 Entospletinib (ENTO) in Combination with Cytarabine (Ara-C) and Daunorubicin (DNR) in Newly Diagnosed (ND) Adult Patients with NPM1-Mutated and FLT3-ITD Wild-Type Acute Myeloid Leukemia (AML) Is Associated with Good Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Combination therapy, Therapies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Uma Borate, MD1, Rui Li, MPH1*, Ying Huang, MS, MA2*, Ronan T. Swords, MD3*, Elie Traer, MD, PhD4, Eytan Stein, MD5, James M. Foran, MD6, Maria R. Baer, MD7, Vu H. Duong, MD, MS7, Wendy Stock, MD8, Olatoyosi Odenike, MD9, Prapti Patel, MD10, Robert H. Collins, M.D.11, Yazan F. Madanat, MD11, Tibor Kovacsovics, MD12, Michael W. Deininger, MD, PhD13, Catherine Smith, MD14, Rebecca L. Olin, MD15, Martha L. Arellano, MD16, William G. Blum, MD17, Gary J. Schiller, MD18, Tara L. Lin, MD19, Matthew C. Foster, MD20, Michael M. Boyiadzis, MD21, Robert L. Redner, MD22, Zeina Al-Mansour, MD23*, Emily K Curran, MD24,25, Nyla A. Heerema, PhD26, Theophilus J Gana, MD PhD27*, Molly Martycz28*, Leonard Rosenberg, PhD RPh29*, Sonja Marcus, MPH30*, Ashley O. Yocum, PhD31*, Timothy Chen, PhD32*, Mona Stefanos28*, Franchesca Druggan, MSc33*, Amy Burd, PhD34, Ross L. Levine, MD35, Brian J. Druker36, John C. Byrd, MD37 and Alice S. Mims, MD2

1Division of Hematology, The Ohio State University, Columbus, OH
2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
3Knight Cancer Institute/ Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, OR
4Knight Cancer Institute, Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR
5Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Division of Hematology/Oncology and Blood and Marrow Transplanation and Cellular Therapy, Mayo Clinic, Jacksonville, FL
7University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
8University of Chicago, Chicago, IL
9Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
10Division of Hematology and Oncology, University of Texas Southwestern, Dallas, TX
11Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX
12Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
13Division of Hematology and Hematologic Malignancies, The University of Utah, Huntsman Cancer Institute, Salt Lake City, UT
14Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, San Francisco, CA
15University of California, San Francisco, San Francisco, CA
16Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
17Department of Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
18David Geffen School of Medicine at UCLA, Los Angeles, CA
19University of Kansas, Westwood, KS
20Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
21Univ. of Pittsburgh Cancer Inst., Pittsburgh, PA
22UPMC Hillman Cancer Center, Pittsburgh, PA
23UF Health Shands Hospital, University of Florida, Gainesville, FL
24Department of Medicine, Section of Hematology/Oncology, University of Chicago, Cincinnati, OH
25University of Cincinnati, Cincinnati, OH
26Department of Pathology, The Ohio State University, Columbus, OH
27Biopharmatech Consulting, Inc., Leesburg, VA
28The Ohio State University Comprehensive Cancer Center, Columbus, OH
29Leukemia & Lymphoma Society, Mount Laurel, NJ
30Leukemia & Lymphoma Society, Rye Brook, NY
31The Leukemia & Lymphoma Society, Rye Brook, NY
32Department of Internal Medicine, Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH
33The Ohio State University, Columbus, OH
34The Leukemia & Lymphoma Society, White Plains, NY
35Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
36Knight Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR
37University of Cincinnati College of Medicine, Cincinnati, OH

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.

Disclosures: Borate: AbbVie/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang: AstraZeneca: Other: Statistical support. Stein: Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; 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; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Bayer: Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy. Foran: Daichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Celgene: Research Funding; DISC Medicine: Research Funding; Roivant: Research Funding; Actinium Pharmaceuticals: Research Funding; Astellas: Research Funding; Astex: Research Funding; Sellas: Research Funding; Pfizer: Research Funding. Baer: AbbVie: Research Funding; Ascentage: Research Funding; Kura Oncology: Research Funding; Kite: Research Funding; Takeda: Research Funding; Forma: Research Funding. Stock: Pluristem: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Kura Oncology: Honoraria; Servier: Honoraria; Syndax: Consultancy, Honoraria; Newave Pharmaceuticals: Consultancy; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria; Kite: 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. Patel: Agios: Membership on an entity's Board of Directors or advisory committees. Madanat: Sierra Oncology, Stemline Therapeutics, Morphosys, Taiho, and Novartis: Membership on an entity's Board of Directors or advisory committees; BluePrint Medicines, GERON, OncLiv: Consultancy, Honoraria. Kovacsovics: Abbvie: Research Funding; Caelum: Research Funding; Gilead: Research Funding; Glycomimetics: Research Funding; Janssen: Research Funding; Jazz Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Syndax: Research Funding; Kite: Honoraria. Deininger: Incyte: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Galena Biopharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria, Research Funding. 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: Astellas: Consultancy; Actinium: Consultancy; Cellectis: Other: NA; Abbvie: Consultancy. Arellano: Syndax Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Schiller: Johnson & Johnson: Current equity holder in publicly-traded company; Takeda: Research Funding; Cellectis: Research Funding; PreCOG LLC: Research Funding; Constellation: Research Funding; Glycomimetics: Research Funding; Actuate: Research Funding; Arog: Research Funding; Millennium: Research Funding; Medimmune: Research Funding; Cellerant: Research Funding; Janssen: Research Funding; Onconova: Research Funding; Tolero: Research Funding; Sangamo: Research Funding; Stemline: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Cyclacel: Research Funding; Kite, a Gilead Company: Research Funding, Speakers Bureau; Amgen: Current equity holder in publicly-traded company, Honoraria; Daiichi-Sankyo: Research Funding; CTI: Research Funding; AVM Biopharma: Research Funding; AltruBio: Research Funding; Gamida: Research Funding; Deltafly: Research Funding; Sellas: Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Trovagen: Research Funding; Novartis: Honoraria, Other: Speaker fees, Research Funding; Forma: Research Funding; Pfizer: Research Funding; Stemline: Research Funding; Geron: Research Funding; Mateon: Research Funding; AstraZeneca: Honoraria; Regimmune: Research Funding; Samus: Research Funding; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Genentech-Roche: Research Funding; Ono Pharma: Honoraria; Deciphera: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Jazz: Consultancy; FujiFilm: Research Funding; Gilead: Research Funding; Astellas: Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria; Actinium: Research Funding; AbbVie: Research Funding, Speakers Bureau. 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: Servier: Consultancy, Honoraria, Other: Participation in advisory board; participation in expert panel guidelines; Tempus: Consultancy, Other: Participation in advisory board; Pfizer: Consultancy, Other: Participation in advisory board; Kite: Consultancy, Other: Participation in advisory board; Incyte: Consultancy, Other: Participation in advisory board; Amgen: Consultancy, Other: Participation in advisory board. Levine: Astra Zeneca and Kura: Other: honoraria for invited lectures ; Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis: Consultancy; Gilead and Novartis: Other: Grant reviews; 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; Qiagen: Other: supervisory board member; Ajax, Abbvie, Constellation, Zenalis, Celgene, Roche, and Prelude: Other: research support. 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: Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Ryvu: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety and Monitoring Board; Syndax: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Other: Data Safety and Monitoring Board; BMS: 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.

*signifies non-member of ASH