Phase i clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer

Isamu Okamoto, Masaki Miyazaki, Ryotaro Morinaga, Hiroyasu Kaneda, Shinya Ueda, Yoshikazu Hasegawa, Taroh Satoh, Akira Kawada, Masahiro Fukuoka, Koichi Fukino, Takahiko Tanigawa, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC]of 6 mg min mL-1) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL-1 and paclitaxel 200 mg/m2 is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.

Original languageEnglish
Pages (from-to)844-853
Number of pages10
JournalInvestigational New Drugs
Volume28
Issue number6
DOIs
Publication statusPublished - Dec 1 2010
Externally publishedYes

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Carboplatin
Paclitaxel
Non-Small Cell Lung Carcinoma
Pharmacokinetics
Area Under Curve
Pharmaceutical Preparations
Erythema Multiforme
Clinical Protocols
Clinical Studies
sorafenib
Alanine Transaminase
Foot
Lung Neoplasms
Pneumonia
Hand
Neoplasm Metastasis
Safety
Skin
Therapeutics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Phase i clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. / Okamoto, Isamu; Miyazaki, Masaki; Morinaga, Ryotaro; Kaneda, Hiroyasu; Ueda, Shinya; Hasegawa, Yoshikazu; Satoh, Taroh; Kawada, Akira; Fukuoka, Masahiro; Fukino, Koichi; Tanigawa, Takahiko; Nakagawa, Kazuhiko.

In: Investigational New Drugs, Vol. 28, No. 6, 01.12.2010, p. 844-853.

Research output: Contribution to journalArticle

Okamoto, I, Miyazaki, M, Morinaga, R, Kaneda, H, Ueda, S, Hasegawa, Y, Satoh, T, Kawada, A, Fukuoka, M, Fukino, K, Tanigawa, T & Nakagawa, K 2010, 'Phase i clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer', Investigational New Drugs, vol. 28, no. 6, pp. 844-853. https://doi.org/10.1007/s10637-009-9321-x
Okamoto, Isamu ; Miyazaki, Masaki ; Morinaga, Ryotaro ; Kaneda, Hiroyasu ; Ueda, Shinya ; Hasegawa, Yoshikazu ; Satoh, Taroh ; Kawada, Akira ; Fukuoka, Masahiro ; Fukino, Koichi ; Tanigawa, Takahiko ; Nakagawa, Kazuhiko. / Phase i clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. In: Investigational New Drugs. 2010 ; Vol. 28, No. 6. pp. 844-853.
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N2 - Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC]of 6 mg min mL-1) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL-1 and paclitaxel 200 mg/m2 is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.

AB - Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC]of 6 mg min mL-1) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL-1 and paclitaxel 200 mg/m2 is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.

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