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27 Phase 3, Multicenter, Open-Label Study of Gilteritinib, Gilteritinib Plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Novel combination therapies in treatment of newly diagnosed AML
Hematology Disease Topics & Pathways:
Adult, Diseases, Therapies, Combinations, Study Population, Clinically relevant, Myeloid Malignancies
Saturday, December 5, 2020: 8:15 AM

Eunice S. Wang, MD1, Pau Montesinos, MD, PhD2,3*, Mark D. Minden4, Je-Hwan Lee, MD, PhD5, Michael Heuser6, Tomoki Naoe, MD, PhD7, Wen-Chien Chou, MD, PhD8, Shufang Liu, PhD9*, Ruishan Wu, MS9*, Nisha Philipose, MS9*, Elizabeth Shima Rich, MD, PhD9 and Ramon V. Tiu, MD10*

1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
2CIBERONC, Instituto Carlos III, Madrid, Spain
3Hospital Universitari i Politècnic La Fe, Valencia, Spain
4Leukemia Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
5Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of (South)
6Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
7National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
8Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
9Astellas Pharma Global Development, Northbrook, IL
10Astellas Pharma, Inc., Northbrook, IL

Background: Gilteritinib is an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor that has demonstrated efficacy with favorable tolerability in patients with FLT3-mutated (FLT3mut+) relapsed/refractory acute myeloid leukemia (AML), including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. Combining FLT3 inhibition with azacitidine (AZA) inhibited tumor growth and induced apoptosis and differentiation of FLT3 ITD AML cell lines and patient blasts in vitro. Further, the combination of gilteritinib with AZA in murine AML xenograft models with FLT3 ITD demonstrated synergy over either treatment alone. We describe an ongoing, phase 3, open-label, randomized trial investigating gilteritinib plus AZA vs AZA alone in adults with newly diagnosed (ND) FLT3mut+ AML who were ineligible for intensive induction chemotherapy (NCT02752035).

Methods: This study is enrolling patients with ND FLT3mut+ (ITD or TKD [D835/I836]) AML who are (a) ≥65 years old and deemed ineligible for intensive induction chemotherapy by the investigator; or (b) ≥18–64 years old with specific comorbidities causing ineligibility for intensive induction chemotherapy. The study was initiated with a Safety Cohort in which patients received oral gilteritinib 80 mg/d as the initial dose on Days 1–28 (or 120 mg/d as the next dose level) plus AZA 75 mg/m2/d on Days 1–7. This was followed by a Randomization Cohort where ~250 patients are planned to be randomized 2:1 to receive oral gilteritinib on Days 1–28 plus AZA 75 mg/m2/d SC/IV on Days 1–7 (Arm AC) or AZA alone, administered in 28-day cycles (Arm C) until lack of efficacy, unacceptable toxicity, or a discontinuation event occurs. An earlier protocol version included a gilteritinib-alone treatment arm (Arm A) that was removed. The primary endpoint is overall survival (OS). Secondary endpoints include event-free survival (EFS; key secondary endpoint), best response, remission rates (complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with partial hematologic remission [CRp], composite CR [CRc; sum of CR, CRi, and CRp]) and duration, transfusion conversion and maintenance rates, leukemia-free survival, patient-reported fatigue, and safety and tolerability. One interim and one final analysis are planned when ~70 and 140 deaths are observed, respectively. OS and EFS will be analyzed using the stratified log-rank test, with strata of age (≥75 vs <75 years), cytogenetic risk (favorable or intermediate vs unfavorable or secondary AML), and FLT3 mutation status (FLT3 TKD vs FLT3 ITD low allelic ratio [<0.5] vs FLT3 ITD high allelic ratio [≥0.5]).

Results Characteristics of all patients enrolled in the Safety and Randomization Cohorts as of 29 June 2020 are presented in Table 1. In the Safety Cohort, 15 patients were enrolled. Fourteen patients have died, and 1 patient continued on treatment (Figure). The median (range) treatment duration was 6 (<1–34) cycles; 40% (n=6/15) received >12 cycles of treatment. Overall, a CRc of 67% (n=10/15) was observed (Figure). Based on these data, a gilteritinib dose of 120 mg daily plus AZA was adopted for the Randomization Cohort. As of 29 June 2020, 136 patients had been randomized with 114 in Arm AC or C and 22 in Arm A (now closed). Median (range) treatment duration was 4 (<1–31) cycles, with 40% (n=54/136) having received ≥6 treatment cycles. A total of 83 patients (61%) in the Randomization Cohort died.

Conclusions: The study is ongoing, and no new safety signals associated with gilteritinib 120 mg daily plus AZA have been observed thus far in the study. Mature remission data from the Safety Cohort of gilteritinib 80-120 mg plus AZA shows a CRc rate of 67%. Patients with ND FLT3mut+ AML considered unfit for intensive chemotherapy continue to be randomized 2:1 to receive gilteritinib 120 mg/d plus AZA vs AZA alone for upfront treatment.

Disclosures: Wang: Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy. Montesinos: Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Lee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Heuser: Pfizer: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy; Bayer: Consultancy, Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Amgen: Research Funding; PriME Oncology: Honoraria; Astellas: Research Funding; Abbvie: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Janssen: Consultancy. Naoe: Sysmex co.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Speakers Bureau. Liu: Astellas: Current Employment. Wu: Astellas: Current Employment. Philipose: Astellas: Current Employment. Rich: Astellas: Current Employment. Tiu: Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

OffLabel Disclosure: New Indication

*signifies non-member of ASH