A phase 1/2 study of gilteritinib in combination with chemotherapy in newly diagnosed patients with AML in Asia

Abstract

Objective: This interim analysis of a phase 1/2, open-label, single-arm study assessed the safety, efficacy, and pharmacokinetics of gilteritinib plus chemotherapy in adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia.

Methods: In sequential phase 1 and 2 studies, induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: idarubicin/cytarabine once daily; consolidation: cytarabine twice daily) was followed by maintenance gilteritinib 120 mg/day monotherapy. Endpoints included maximum tolerated dose (MTD), recommended expansion dose (RED), and dose-limiting toxicity (phase 1), and complete remission (CR) rate following induction therapy (primary endpoint), overall survival (OS), safety, and pharmacokinetics (phase 2).

Results: In phase 1, MTD was not reached and RED was 120 mg/day. In phase 2, the CR rate was 50.0% after induction (90% confidence interval [CI] 40.4, 59.6); however, the lower confidence limit did not exceed the pre-defined 55% benchmark. Composite CR (CRc) rates were high following induction (86.6%, 95% CI [77.3, 93.1]), consolidation, and maintenance therapy (87.8%, 95% CI [78.7, 94.0], each). The probability of OS was 86.6% at 12 months. No new safety findings were reported.

Conclusion: In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.

Keywords: FLT3 mutation; Acute myeloid leukemia; Chemotherapy; Gilteritinib; Newly diagnosed.

Fig. 1

Study flow diagram [1] Cycle 1 was to be started without delay when a patient had reached remission with blood count recovery (within 57 days from the start of the last cycle of induction therapy). Subsequent cycles were to be started after completion of the assessment on Day 28 of the previous cycle; subsequent cycles were to be started after Day 22 of the previous cycle, following recovery of the patient’s blood count. [2] Treatment was allowed to be started on the day informed consent was obtained when the investigator or subinvestigator judged that immediate treatment was required due to rapid proliferative disease progression. In this case, among the test items specified in both screening and Day 1 of Cycle 1, tests to determine body height, body weight, vital signs, and ECOG PS and laboratory tests were not required to be performed twice. [3] Consent, screening, and Cycle 1 Day 1 of the induction period were allowed to be performed on the same day if investigator(s) judged that it would be necessary due to rapid disease progression and patient met all inclusion/exclusion criteria for pre-registration, except the following inclusion criteria: FLT3-ITD and/or TKD mutation positive, AST/ALT <3 x ULN, serum magnesium ≥ institutional LLN. Cycle 1 Day 1 had to be initiated within 7 days of consent. [4] Number of days in 1 cycle was not defined in the phase 2 part. Each cycle was allowed to be extended until blood recovery was observed. Timing to initiate the second cycle or next treatment period was determined by investigators based on patient condition. [5] Patients had to fulfill all inclusion and exclusion criteria by the end of Day 7 in order to complete registration on Day 8. [6] Patients who were eligible for HSCT were allowed to receive HSCT without consolidation therapy. Patients who received HSCT were allowed to return to the study if the following conditions were met: patient was 30–90 days post-HSCT, patient had successful engraftment as demonstrated by ANC ≥500/mm3 and platelets ≥20000/mm3 without transfusions; patient did not have ≥Grade 2 acute GVHD; and patient was in CRc. [7] Follow-up period was 3 years from treatment initiation for the last enrolled patient or completion of 30-day follow-up of the last patient(s), whichever was longer. [8] Preferably, the following cycle was started after full hematologic recovery (defined as neutrophil count ≥1000/mm3, platelet count ≥100,000/mm3), allowing formal assessment of response. [9] Patients who achieved full hematologic recovery prior to Day 42 were preferred to perform the Day 42 scheduled visit for patient safety. If the patient achieved more than a partial remission, the patient was allowed to continue to the next therapy or proceed to HSCT. If refractory disease was confirmed, scheduled visits were allowed to be skipped to perform Cycle 2 of induction therapy. ALT; alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; DLT, dose limiting toxicity; ECOG, Eastern Cooperative Oncology Group; HSCT, hematopoietic stem cell transplantation; ITD, internal tandem duplication; LLN, lower limit of normal; PS, performance status; TKD, tyrosine kinase domain; ULN, upper limit of normal

Fig. 2

CRc rates after each treatment period (FAS) CR, complete remission; CRc, composite complete remission rate; CRi, complete remission with incomplete hematological recovery; CRp, complete remission with incomplete platelet recovery; FAS, full analysis set

Fig. 3

Kaplan-Meier plot of OS (a), EFS (b) and RFS (c) (TTE-FAS) EFS, event-free survival; OS, overall survival; RFS, relapse-free survival; TTE-FAS, time-to-event full analysis set