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

Background: Gilteritinib is an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor that has demonstrated efficacy with favorable tolerability in patients with FLT3-mutated (FLT3^mut+) 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) FLT3^mut+ AML who were ineligible for intensive induction chemotherapy (NCT02752035).

Methods: This study is enrolling patients with ND FLT3^mut+ (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 FLT3^mut+ 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.