Background: GILT is a potent oral selective FLT3 kinase inhibitor ( FLT3i) approved for the treatment of patients with relapsed/refractory FLT3 mutated ( FLT3m) AML. However, the optimal combination in older, newly diagnosed (ND) FLT3m AML patients is unknown. GILT in combination with azacitidine (AZA) had higher initial response rates, but did not improve overall survival (OS), compared to placebo in the LACEWING trial (Wang et al. Blood 2021). GILT followed by decitabine (DEC) was also tested and found to be safe, but the efficacy did not meet pre-determined criteria (NCT03013998, S8 Group 1). In the interim, VEN + AZA/DEC emerged as the new standard of care for older/unfit patients with AML (DiNardo et al. NEJM 2020). Thus, the Beat AML S8 study was amended to assess the safety and efficacy of GILT in combination with DEC and VEN in newly diagnosed FLT3m AML patients aged ≥60 years (NCT03013998, S8 Group 2).
Methods: The S8 Group 2 sub-study was part of the multicenter (15 sites) Beat AML Master Trial. Key eligibility criteria included ND FLT3m AML patients aged ≥60 years who are not able to receive intensive induction chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. A conventional 3+3 design was used to determine the recommended phase 2 dose (RP2D) of GILT+DEC+VEN. Patients were treated with GILT at three dose levels (DL). During induction, treatment consisted of GILT 120mg/day on days 1-7 then 80mg/day on days 8-28 for dose level 1 (DL1), or on days 8-21 (DL-1), or on days 8-14 (DL-2). All patients received DEC at 20mg/m 2 on days 8-12, and VEN at 400mg/day (or at 100mg/day if concomitant antifungal) on days 8-28. Patients who achieved a complete remission (CR) or CR with hematologic improvement (CRh) received GILT 80mg/day on days 1-15 (DL1) or days 1-7 (DL-1, DL-2), DEC on days 1-5 (All DLs), and VEN on days 1-15 (DL1, DL-1) or days 1-10 (DL-2) for an additional 12 consolidation cycles. The primary end point was to determine the tolerability and toxicity of GILT in combination with DEC and VEN. Secondary end point was the composite CR (CRc: CR/CRh) rate. Response was assessed using modified 2017 European LeukemiaNet (ELN) AML criteria.
Results: Between 10/22/2020 and 6/13/2022, 19 patients were consented, of whom 18 started treatment and were included in the analysis. The median age was 73 and baseline patient characteristics are shown in Table 1. The first 2 patients treated at DL1 both experienced hematologic dose-limiting toxicities (DLTs) with persistently low absolute neutrophil count (ANC). Therefore, the GILT dose was de-escalated to DL-1, where 8 patients were enrolled and treated. Among the 6 evaluable patients on DL-1, DLTs occurred in 2 patients; one had hematologic DLT and the other had failure to thrive. This led to dose de-escalation to DL-2. In DL-2, 2/8 patients experienced hematologic DLTs. The protocol was then amended to include DL-3 and DL-4, but the trial was closed by the sponsor due to priority transition and enrollment was halted so further dose reductions were not evaluated. Adverse events (AEs) were mostly hematologic, and 11 patients had treatment-related adverse events (TAEs), 10 of them grade 3 or higher. Median (range) time on treatment was 6 (1-25) cycles. Most common reason for treatment discontinuation were adverse event (3, 21.4%), recurrence (2, 14.3%), stem cell transplant (2, 14.3%), and death (2, 14.3%)
Nine patients achieved CR, 2 patients achieved CRh and 1 patient achieved complete remission with incomplete hematologic recovery (CRi). The CRc rate (CR/CRh) was 61.1% (11/18, 95% CI: 38.6%-83.6%). After a median follow up of 19.7 months, the median overall survival and duration of response were not reached. One-year overall survival (OS) was 71.8% (95% CI: 44.9-87.2).
Conclusion: Triplet therapy of GILT+DEC+VEN inND FLT3m AML patients ≥60 years old induced a high response rate (CRc rate 61.1%), and the median OS was not reached at time of this report (median follow-up 19.7 months). The typical dose of GILT 120mg/day with DEC+VEN was associated with significant hematology toxicities, which required multiple dose level reductions. At the reduced dose (GILT 80mg/day on days 1-7), the combination therapy was generally safe and well tolerated. A Phase 2 clinical trial sponsored by Astellas of GILT+AZA+VEN as frontline treatment for ND older patients with FLT3m AML is now enrolling (NCT05520567).
Funding: this study was funded by Astellas Pharma Inc.
Disclosures
Swords:Kronos Bio: Research Funding. Lin:Bio-path Holdings: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Celyad: Research Funding; Aptevo Therapeutics: Research Funding; Cleave Biosciences: Research Funding; Ciclomed: Research Funding; Jazz Pharmaceuticals: Research Funding. Madanat:Blueprint Medicines: Consultancy, Honoraria, Other: travel reimbursement; MD Education: Honoraria; OncLive: Honoraria; Novartis: Honoraria; Taiho oncology: Honoraria; Stemline therapeutics: Honoraria; Morphosys: Honoraria, Other: travel reimbursement; Sierra Oncology: Honoraria; GERON: Consultancy; Rigel Pharmaceuticals: Honoraria. Patel:Servier LLC: Current Employment. Baer:Kite, a Gilead company (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; FORMA Therapeutics (Inst): Research Funding; Kura Oncology (Inst): Research Funding; Takeda (Inst): Research Funding; Abbvie (Inst): Research Funding. Kovacsovics:Servier: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Syndax Pharmaceuticals: Research Funding. Olin:Cellectis: Research Funding; Servier: Consultancy; Actinium: Consultancy; Rigel: Consultancy; Abbvie: Consultancy; Astellas: Consultancy. Curran:Kite: Other: Advisory board; Amgen: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Honoraria, Other: Advisory board; Jazz: Other: Advisory board; Servier: Consultancy, Other: Expert consensus panel. Stein:Foghorn: Consultancy; Servier: Consultancy; Calithera: Consultancy; Eisai: Research Funding; Bristol Myers Squib: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi: Consultancy; Aptose: Consultancy; Syros: Consultancy; Novartis: Consultancy; PinotBio: Consultancy; Janssen: Consultancy; Agios: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Ono Pharma: Consultancy; Blueprint: Consultancy; OnCusp: Consultancy; Syndax: Consultancy; Gilead: Consultancy; Neoleukin: Consultancy; Abbvie: Consultancy; Genesis: Consultancy; Genentech: Consultancy; Menarini: Consultancy. Schiller:Geron: Research Funding; ElevateBio: Research Funding; Agios: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Takeda: Research Funding; Stemline Therapeutics: Research Funding; Sellas Life Sciences: Research Funding; Sangamo Bioscience: Research Funding; Samus Therapeutics: Research Funding; REGiMMUNE: Research Funding; Precog: Research Funding; Pfizer: Research Funding; Onconova Therapeutics: Research Funding; Mateon Therapeutics: Research Funding; Genentech/Roche: Research Funding; Gamida Cell: Research Funding; Fujifilm: Research Funding; FORMA Therapeutics: Research Funding; Delta-Fly Pharma: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; Arog: Research Funding; Actuate Therapeutics: Research Funding; Actinium Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Kite: Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Agios: Consultancy; Ono Pharmaceutical: Consultancy; Ono Pharmaceutical: Research Funding; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Kronos Bio: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau. Zeidner:Stemline: Research Funding; Shattuck Labs: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Immunogen: Honoraria; Jazz: Research Funding; Merck: Research Funding; Novartis: Consultancy; Sellas: Consultancy; Astex: Research Funding; Daiichi Sankyo: Honoraria; Foghorn: Consultancy; Gilead: Consultancy, Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Arog: Research Funding; Takeda: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levine:Auron: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Lilly: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Prelude: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Ajax: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria. Druker:Labcorp: Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy, Current holder of stock options in a privately-held company; US Patent and Trademark Office: Patents & Royalties: Patents 6958335 (Novartis exclusive license), 4326534, 7416873, 7592142, 10473667, 10664967, 11049247; Gilead: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Nemucore Medical Innovations, Inc.: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Astellas: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Therapy Architects, LLC: Membership on an entity's Board of Directors or advisory committees; Syndax: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; AstraZeneca: Other: PI or Co-investigator on clinical trial(s) funded via contract with OHSU.; Enliven Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Current Employment, Patents & Royalties: #1518 (exclusive option agreement with CytoImage); #0606/Patent 6958335 (Novartis exclusive license); #2573; #0843; #0996; The RUNX1 Research Foundation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; Vincerx Pharma, Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Beat AML LLC: Membership on an entity's Board of Directors or advisory committees; Multicancer Early Detection (MCED) Consortium: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; CureOne: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: PI or Co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Celgene: Other: Co-investigator on clinical trial(s) funded via contract with OHSU.; DNA SEQ: Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties: #2063 (licensed exclusively to Merck & Co); and #2524, Research Funding; GRAIL: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Cepheid: 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; Blueprint Medicines: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adela, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Burd:Eilean Theraputics: Current Employment, Current equity holder in private company. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Borate:Kura: Membership on an entity's Board of Directors or advisory committees; Incyte: Other; Jazz: Other: Research; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Research; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Research; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; RUNX1 Foundation: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Byrd:Vincerx: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Kurome: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees, Research Funding; Orbimed: Consultancy, Research Funding; Orange Grove Bio: Membership on an entity's Board of Directors or advisory committees; OSU Drug Devel. Inst.: Consultancy; Eilean Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Cancer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Traer:Schrodinger: Research Funding; Astra-Zeneca: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees.
