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 advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group.

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/m(2) on day 1 and gemcitabine 1250 mg/m(2) 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.