Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer

Takashi Seto, Fumihiko Hirai, Hideo Saka, Yoshihito Kogure, Kiyotaka Yoh, Seiji Niho, Kenjiro Fukase, Hitoshi Shimada, Michitaka Sasai, Koichi Fukino

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Abstract

Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. Results: Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. Conclusions: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.

Original languageEnglish
Pages (from-to)31-42
Number of pages12
JournalJapanese journal of clinical oncology
Volume48
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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docetaxel
Non-Small Cell Lung Carcinoma
Safety
Neoplasms
Therapeutics
AZD 6244
Pharmacokinetics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. / Seto, Takashi; Hirai, Fumihiko; Saka, Hideo; Kogure, Yoshihito; Yoh, Kiyotaka; Niho, Seiji; Fukase, Kenjiro; Shimada, Hitoshi; Sasai, Michitaka; Fukino, Koichi.

In: Japanese journal of clinical oncology, Vol. 48, No. 1, 01.01.2018, p. 31-42.

Research output: Contribution to journalArticle

Seto, Takashi ; Hirai, Fumihiko ; Saka, Hideo ; Kogure, Yoshihito ; Yoh, Kiyotaka ; Niho, Seiji ; Fukase, Kenjiro ; Shimada, Hitoshi ; Sasai, Michitaka ; Fukino, Koichi. / Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. In: Japanese journal of clinical oncology. 2018 ; Vol. 48, No. 1. pp. 31-42.
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abstract = "Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. Results: Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. Conclusions: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.",
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T1 - Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer

AU - Seto, Takashi

AU - Hirai, Fumihiko

AU - Saka, Hideo

AU - Kogure, Yoshihito

AU - Yoh, Kiyotaka

AU - Niho, Seiji

AU - Fukase, Kenjiro

AU - Shimada, Hitoshi

AU - Sasai, Michitaka

AU - Fukino, Koichi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. Results: Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. Conclusions: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.

AB - Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. Results: Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. Conclusions: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.

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