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

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Authors: Masashi Sawa ; Toshihiro Miyamoto ; Hee-Je Kim ; Yasushi Hiramatsu ; June-Won Cheong ; Takayuki Ikezoe ; Tomoki Naoe ; Koichi Akashi ; Satoshi Morita ; Masanori Kosako ; Moyu Ikegaya ; Wataru Terada ; Takeshi Kadokura ; Jason Hill ; Shuichi Miyawaki ; Stanley C Gill ; Alexandra Heinloth ; Nahla Hasabou

MeSH: Adult ; Aged ; Aniline Compounds* / administration & dosage ; Aniline Compounds* / adverse effects ; Aniline Compounds* / pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols* / administration & dosage ; Antineoplastic Combined Chemotherapy Protocols* / adverse effects ; Antineoplastic Combined Chemotherapy Protocols* / pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols* / therapeutic use ; Cytarabine / administration & dosage ; Cytarabine / adverse effects ; Female ; Humans ; Idarubicin / administration & dosage ; Idarubicin / adverse effects ; Leukemia, Myeloid, Acute* / diagnosis ; Leukemia, Myeloid, Acute* / drug therapy ; Leukemia, Myeloid, Acute* / genetics ; Leukemia, Myeloid, Acute* / mortality ; Male ; Maximum Tolerated Dose ; Middle Aged ; Mutation ; Pyrazines* / administration & dosage ; Pyrazines* / adverse effects ; Pyrazines* / pharmacokinetics ; Treatment Outcome ; Young Adult ; fms-Like Tyrosine Kinase 3 / genetics

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

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.