A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

Background: Gilteritinib, an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, demonstrated antileukemic responses in patients with FLT3-mutated (FLT3^mut+) relapsed/refractory acute myeloid leukemia (AML). We report final results from a phase 1 study of once-daily oral gilteritinib plus intravenous (IV) chemotherapy in patients with newly diagnosed AML.

Methods: This 4-part, open-label, phase 1 study (NCT02236013) assessed the safety/tolerability and antileukemic effects of gilteritinib plus 7+3 induction and high-dose cytarabine consolidation chemotherapy, and as single-agent maintenance therapy in adults with newly diagnosed AML. In part 1, successive cohorts of 3–6 patients received 40–200 mg/d gilteritinib (Days 4–17) and ≤2 cycles of induction (cytarabine 100 mg/m²/d IV, Days 1–7; idarubicin 12 mg/m²/d IV, Days 1–3). In part 2, patients (n=33, of which at least 15 were FLT3^mut+) received the recommended 120 mg/d gilteritinib expansion dose and ≤2 cycles of the part 1 induction schedule. In part 3, patients were stratified into 2 cohorts: one receiving treatment from part 2 (n=7) and the other receiving treatment that replaced idarubicin with daunorubicin (90 mg/m²/d IV, Days 1–3; n=7). In part 4, patients (n=12) received the same induction as the part 3/daunorubicin cohort (with a reduction in cycle 2 to daunorubicin 45 mg/m²/d). During consolidation, patients received ≤3 cycles of cytarabine (1.5 g/m² every 12 hours; Days 1, 3, and 5) and gilteritinib (Days 1–14 for parts 1–3; Days 1–56 for part 4) at the induction dose. Gilteritinib was given once daily in 28-day cycles for up to 26 cycles as maintenance therapy (maintenance phase is still ongoing). Patients achieving composite complete remission (CRc) or partial remission could undergo hematopoietic stem cell transplant (HSCT) and resume maintenance gilteritinib treatment post-HSCT.

Results: As of 23 June 2020, 80 patients were allocated to treatment (safety analysis set, n=79); median age was 59.0 y (range, 23–77) and most were male (62.0%). Median follow-up for overall survival (OS) was 35.8 mo. Dose-limiting toxicities are provided in Table 1. The maximum tolerated dose was 120 mg/d. Serious treatment-related adverse events (AEs) and AEs leading to discontinuation of gilteritinib occurred in 12.7% (n=10) and 5.1% (n=4) of patients, respectively. One (1.3%) death occurred across all treatment phases. Grade ≥3 nonhematologic AEs (≥10% of patients) were increased alanine aminotransferase (13.9%), pneumonia (13.9%), sepsis (11.4%), and bacteremia (11.4%). At the end-of-induction time point, there were 44 (55.7%) total FLT3^mut+ patients across all dose groups and 38 (48.1%) patients who received gilteritinib 120 mg/d. Investigator-reported CRc was achieved by 81.8% of patients across all dose groups (n=36) and 81.6% among patients who received gilteritinib 120 mg/d (n=31; Table 2). Anthracycline choice had no clear impact on CRc rate, although the number of patients in these cohorts was low. In FLT3^mut+ patients who achieved CRc in any dose group, median (95% CI) duration of CRc and disease-free survival were 14.1 (4.0–29.9) and 15.3 (9.8–not reached) mo, respectively. Median OS for FLT3^mut+ patients has not been reached. The survival probability (95% CI) in all FLT3^mut+ patients at weeks 8, 12, 26, 52, and 104 were 97.7% (84.6%–99.7%), 95.3% (82.5%–98.8%), 92.9% (79.6%–97.7%), 83.1% (67.7%–91.5%), and 71.8% (54.6%–83.4%), respectively. In patients with FLT3 internal tandem duplication (ITD)-positive AML achieving CRc, mutational clearance (summed FLT3 ITD signal ratio of ≤10^-4 after induction or consolidation) was achieved by 70% (n/N=16/23) of patients receiving a gilteritinib dose of ≥120 mg. HSCT occurred in 30.4% of the total population (n/N=24/79). Analysis of plasma inhibitory activity and pharmacokinetics of gilteritinib will be available at presentation.

Conclusions: Gilteritinib plus induction and consolidation chemotherapy is well tolerated in patients with newly diagnosed AML. Favorable antileukemic responses were observed in FLT3^mut+ patients regardless of anthracycline type or gilteritinib administration schedule, with a mutational clearance rate of 70.0%. Based on these results, randomized clinical trials of induction and consolidation chemotherapy plus gilteritinib vs midostaurin in FLT3^mut+ AML patients have been initiated.