Updated Results from a Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: Pratz Keith W. , Cherry Mohamad , Altman Jessica K. , Cooper Brenda , Cruz Jose Carlos , Jurcic Joseph G. , Levis Mark J. , Lin Tara L , Perl Alexander E. , Podoltsev Nikolai A. , Schiller Gary J. , Liu Chaofeng , Bahceci Erkut 
Published: October 2019

Abstract
Introduction: Gilteritinib is a novel, potent, highly-selective oral fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor. Once-daily single-agent gilteritinib doses of ≥80 mg/day elicited antileukemic responses in FLT3 mutation-positive (FLT3mut+) subjects with relapsed/refractory AML (Perl AE, et al. Lancet Oncol. 2017). We examined the safety/tolerability and antitumor activity of gilteritinib plus front-line intensive chemotherapy in newly diagnosed AML patients.
Methods: This ongoing open-label, dose-escalation/expansion phase 1 study (NCT02236013) assesses the safety/tolerability and antitumor effects of gilteritinib combined with 7+3 induction and high-dose cytarabine consolidation, and as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML (excluding core-binding factor translocations). Dose escalation followed a 3+3 design; successive cohorts of 3-6 subjects received 40, 80, 120, or 200 mg/day gilteritinib. Subjects received ≤2 cycles of a 7+3 induction regimen (cytarabine 100 mg/m2/day, Days 1-7 plus idarubicin 12 mg/m2/day, Days 1-3 [dose-escalation and dose-expansion cohorts], and once-daily gilteritinib on Days 4-17 [Schedule 1]). After completion of the dose-expansion cohort using Schedule 1, a new cohort of patients were enrolled. In this cohort of six patients, gilteritinib administration was changed to Days 8-21 (Schedule 2) in preparation for phase 3 studies and daunorubicin 90 mg/m2/day, administered on Days 1-3, was used as an alternative anthracycline to idarubicin. During consolidation, subjects received cytarabine (1.5 g/m2 every 12 hours, Days 1, 3, and 5) and once-daily gilteritinib (Days 1-14) at the induction dose for ≤3 cycles. Subjects in the dose-expansion cohort received gilteritinib at the recommended expansion dose established during dose escalation. Transplantation was allowed for responding subjects. After consolidation or transplantation with stable engraftment, subjects received maintenance therapy with once-daily gilteritinib (28-day cycles; ≤26 cycles).
Results: As of July 2, 2018, 62 subjects have been enrolled; 60 are included in the safety analysis set. Most subjects were male (66.7%; median age, 59.5 years [range, 23-77]) and 32 (53.3%) had FLT3 mutations (FLT3-ITD, n=23). During dose-escalation, two subjects in the 40 mg/day cohort who had received gilteritinib on Days 1-14 experienced dose-limiting toxicities (DLTs; neutropenia, thrombocytopenia, decreased ejection fraction). After the gilteritinib induction schedule change, no more DLTs occurred at this dose. Two subjects in the 200 mg/day cohort experienced DLTs (neutropenia, neutropenic enterocolitis). The maximum tolerated dose and the recommended expansion dose were established at 120 mg/day. Grade ≥3 adverse events (AEs) in ≥10% of patients were febrile neutropenia (63.3%), thrombocytopenia (18.3%), decreased platelet count (16.7%), neutropenia (15.0%), bacteremia (10.0%), sepsis (10.0%), and decreased white blood cell count (10.0%). Serious drug-related AEs in >1 subject were febrile neutropenia (n=9), small intestinal obstruction, lung infection, sepsis, and decreased ejection fraction (all n=2). The end-of-treatment investigator-reported rate of composite complete remission (CRc) for response evaluable FLT3mut+ subjects receiving gilteritinib 120 mg on Schedule 1 (n=17) was 100%. The CRc rate in FLT3mut+ subjects receiving Schedule 2 induction with daunorubicin was also 100% (Table). Enrollment in the Schedule 2 cohort receiving idarubicin is ongoing; the two subjects in this cohort have not been assessed for response. Among subjects who received ≥80 mg/day gilteritinib (n=47), CRc rates for FLT3mut+ subjects were 88.9% (n=24/27). Median overall survival has not been reached. Median disease-free survival was 297 days (95% CI: 112, not reached). Assessment of minimum residual disease in FLT3-ITD patients using a next-generation sequencing-based assay is ongoing; results will be available at the time of presentation.
Conclusions: Gilteritinib can be safely combined with intensive chemotherapy, and given as single-agent maintenance therapy in subjects with newly diagnosed AML. Treatment was well tolerated. High response rates were observed in FLT3mut+ subjects after treatment with either idarubicin or daunorubicin in combination with two different gilteritinib administration schedules.

Disclosures
Pratz: Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Altman:Astellas Pharma: Other; Agios: Other: Payment to the institution to conduct the trial ; Epizyme: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; GSK: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Cruz:Takeda: Speakers Bureau. Jurcic:Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Celgene: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Actinium Pharmaceuticals, Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding; Genetech: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Research Funding. Lin:Jazz Pharmaceuticals: Honoraria. Perl:AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Research Funding; LAM Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Sunesis Pharmaceuticals: Research Funding; Daiichi Snakyo: Research Funding; Celator: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astellas Pharma: Employment. Bahceci:Astellas Pharma: Employment.