Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors
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A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.
In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).
There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).
The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.
KeywordsPazopanib Lapatinib Japanese patients Phase 1 Pharmacokinetics
Appreciation is expressed to the patients and their families, as well as the many investigators who participated in the study.
This study was approved by the appropriate ethics committee(s), was performed in accordance with the Declaration of Helsinki, and complied with the current laws of the country (Japan) in which it was conducted. All patients provided informed consent before inclusion in the study.
Conflict of interest
This study (VEG109693; NCT00516672) was supported by research funding from GlaxoSmithKline Pharmaceuticals. Editorial assistance was provided by ProEd Communications, Inc., Beachwood, Ohio, USA, and was supported by GlaxoSmithKline. Akiko Takekura is employee but not stockholder of GSK. Kazuo is employee and stockholder of GSK. Yasutsuna Sasaki served as a consultant/advisor for Takeda-Bio, Kowa, and GlaxoSmithKline. Yuichi Ando served as a consultant/advisor for GlaxoSmithKline. The other authors have no conflicts of interest to disclose concerning this study.
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