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01-07-2014 | Original Article

A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC)

Authors: Hidehito Horinouchi, Noboru Yamamoto, Hiroshi Nokihara, Takeshi Horai, Makoto Nishio, Fumiyoshi Ohyanagi, Atsushi Horiike, Kazuhiko Nakagawa, Masaaki Terashima, Takafumi Okabe, Hiroyasu Kaneda, Mark D. McKee, Dawn M. Carlson, Hao Xiong, Tomohide Tamura

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2014

Abstract

Introduction

Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC.

Methods

Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients.

Results

Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib C _max was 0.32 μg/mL and AUC₂₄ was 4.29 μg h/mL. Linifanib C _max occurred at 2–3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients.

Conclusions

Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.

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Title: A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC)
Authors: Hidehito Horinouchi
Noboru Yamamoto
Hiroshi Nokihara
Takeshi Horai
Makoto Nishio
Fumiyoshi Ohyanagi
Atsushi Horiike
Kazuhiko Nakagawa
Masaaki Terashima
Takafumi Okabe
Hiroyasu Kaneda
Mark D. McKee
Dawn M. Carlson
Hao Xiong
Tomohide Tamura
Publication date: 01-07-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2478-9

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