Phase I and pharmacokinetic study of gefitinib and S-1 combination therapy for advanced adenocarcinoma of the lung
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ORIGINAL ARTICLE
Phase I and pharmacokinetic study of gefitinib and S-1 combination therapy for advanced adenocarcinoma of the lung Hidemi Kiyota • Isamu Okamoto • Masayuki Takeda • Haruko Daga • Tateaki Naito • Masaki Miyazaki • Hideaki Okada • Hidetoshi Hayashi • Kaoru Tanaka • Masaaki Terashima • Koichi Azuma • Haruyasu Murakami • Koji Takeda • Nobuyuki Yamamoto • Kazuhiko Nakagawa
Received: 4 May 2012 / Accepted: 1 January 2013 / Published online: 20 January 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Background A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Methods Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1–14 every 21 days at doses starting at 60 mg/m2 (level 1) and escalating to 80 mg/m2 (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Results Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a doselimiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median
H. Kiyota I. Okamoto (&) M. Takeda M. Miyazaki H. Hayashi K. Tanaka M. Terashima K. Azuma K. Nakagawa Department of Medical Oncology, Faculty of Medicine, Kinki University, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan e-mail: [email protected] H. Daga H. Okada K. Takeda Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan T. Naito H. Murakami N. Yamamoto Thoracic Oncology Division, Shizuoka Cancer Center, Shizuoka, Japan
progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation–positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. Conclusions The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation–positive NSCLC. Keywords Gefitinib S-1 Non-small-cell lung cancer Epidermal growth factor receptor Phase I study
Introduction Gefitinib was the first molecularly targeted agent to become clinically available for the treatment of non-smallcell lung cancer (NSCLC). Somatic activating mutations of EGFR have been identified as a major determinant of the clinical response to treatment with gefitinib, with achievement of a clinical benefit with this drug in NSCLC patients with wild-type EGFR having been p
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