Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia

An open-label phase 1 study

Kensuke Usuki, Toru Sakura, Yukio Kobayashi, Toshihiro Miyamoto, Hiroatsu Iida, Satoshi Morita, Erkut Bahceci, Masahito Kaneko, Mikiko Kusano, Shunsuke Yamada, Shigeru Takeshita, Shuichi Miyawaki, Tomoki Naoe

Research output: Contribution to journalArticle

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Abstract

Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.

Original languageEnglish
Pages (from-to)3235-3244
Number of pages10
JournalCancer Science
Volume109
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Acute Myeloid Leukemia
fms-Like Tyrosine Kinase 3
Maximum Tolerated Dose
Creatine Kinase
Blood Platelets
Pharmacokinetics
Tumor Lysis Syndrome
Syncope
Amylases
L-Lactate Dehydrogenase
Safety
Pharmaceutical Preparations
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia : An open-label phase 1 study. / Usuki, Kensuke; Sakura, Toru; Kobayashi, Yukio; Miyamoto, Toshihiro; Iida, Hiroatsu; Morita, Satoshi; Bahceci, Erkut; Kaneko, Masahito; Kusano, Mikiko; Yamada, Shunsuke; Takeshita, Shigeru; Miyawaki, Shuichi; Naoe, Tomoki.

In: Cancer Science, Vol. 109, No. 10, 01.10.2018, p. 3235-3244.

Research output: Contribution to journalArticle

Usuki, K, Sakura, T, Kobayashi, Y, Miyamoto, T, Iida, H, Morita, S, Bahceci, E, Kaneko, M, Kusano, M, Yamada, S, Takeshita, S, Miyawaki, S & Naoe, T 2018, 'Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study', Cancer Science, vol. 109, no. 10, pp. 3235-3244. https://doi.org/10.1111/cas.13749
Usuki, Kensuke ; Sakura, Toru ; Kobayashi, Yukio ; Miyamoto, Toshihiro ; Iida, Hiroatsu ; Morita, Satoshi ; Bahceci, Erkut ; Kaneko, Masahito ; Kusano, Mikiko ; Yamada, Shunsuke ; Takeshita, Shigeru ; Miyawaki, Shuichi ; Naoe, Tomoki. / Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia : An open-label phase 1 study. In: Cancer Science. 2018 ; Vol. 109, No. 10. pp. 3235-3244.
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abstract = "Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7{\%}]) and increased blood creatine phosphokinase (n = 3 [12.5{\%}]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80{\%} (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20{\%}]; CR with incomplete hematologic recovery, 2 [40{\%}]; partial remission (PR), 1 [20{\%}]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4{\%}; (n = 4 of 11; CR, 1 [9.1{\%}]; CR with incomplete platelet recovery, 2 [18.2{\%}]; PR, 1 [9.1{\%}]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.",
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AU - Miyamoto, Toshihiro

AU - Iida, Hiroatsu

AU - Morita, Satoshi

AU - Bahceci, Erkut

AU - Kaneko, Masahito

AU - Kusano, Mikiko

AU - Yamada, Shunsuke

AU - Takeshita, Shigeru

AU - Miyawaki, Shuichi

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N2 - Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.

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