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Clin Pharmacol Drug Dev ; 13(5): 560-571, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38284515

RESUMO

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzotiazóis , Quimioterapia de Consolidação , Leucemia Mieloide Aguda , Compostos de Fenilureia , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , China , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Benzotiazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto , Japão , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Quimioterapia de Consolidação/efeitos adversos , Quimioterapia de Consolidação/métodos , Idoso , Quimioterapia de Indução/métodos , Relação Dose-Resposta a Droga
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