A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advance

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• 作者：Glenwood Goss ; Frances A. Shepherd ; Scott Laurie ; Isabelle Gauthier ; N. Leighl ; Eric Chen ; Ronald Feld ; Jean Powers ; Lesley Seymour
• 关键词：Cebiranib ; Chemotheraphy ; Non small cell lung cancer ; Phase I
• 刊名：European Journal of Cancer
• 出版年：2009
• 出版时间：March 2009
• 年：2009
• 卷：45
• 期：5
• 页码：782-788
• 全文大小：136 K

文摘

Introduction

Cediranib, a potent vascular endothelial growth factor inhibitor, demonstrated broad pre-clinical anti-tumour activity. This study evaluated escalating cediranib doses with combination chemotherapy in advanced non-small cell lung cancer patients.

Methods

Patients received cisplatin 80 mg/m² on day 1 and gemcitabine 1250 mg/m² on days 1 and 8 of a 3-week cycle, and daily oral cediranib at either 30 mg or 45 mg. Pharmacokinetics of all drugs were analysed, and response was assessed by RECIST.

Results

Fifteen patients were enrolled. No dose-limiting toxicities were observed during cycle 1. Fatigue, nausea, diarrhoea, anorexia and granulocytopaenia were common; hypertension was manageable. No grade 3/4 bleeding occurred. At 45 mg/d, fatigue, diarrhoea and thrombocytopaenia were increased; and headache, hoarseness and grade 2 hand–foot syndrome were observed. Cediranib had no effect on cisplatin elimination, but clearance of gemcitabine is significantly reduced in the presence of cediranib (p > 0.02). Central review confirmed responses in four of 15 enrolled patients (26.7 % , 95 % CI 7.8–55 % ) and four of 12 evaluable patients (33.3 % , 95 % CI 9.9–65 % ).

Conclusion

Cediranib at 30 mg daily can be combined with standard doses of cisplatin/gemcitabine with encouraging anti-tumour activity, and is the recommended phase III dose. Toxicity is increased, but is predictable and manageable.