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.

Abstract

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.

• Authors: Glenwood Goss, Frances A Shepherd, Scott Laurie, Isabelle Gauthier, N Leighl, Eric Chen, Ronald Feld, Jean Powers, Lesley Seymour
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 45 Issue 5 Pg. 782-8 (Mar 2009) ISSN: 1879-0852 [Electronic] England
• PMID: 19091548 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Quinazolines
• Deoxycytidine
• cediranib
• Cisplatin
• Gemcitabine

Topics

• Administration, Oral
• Adult
• Aged
• Angiogenesis Inhibitors (administration & dosage, adverse effects, blood)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, blood, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (blood, drug therapy, pathology)
• Cisplatin (administration & dosage, adverse effects, blood)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, blood)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Hematologic Diseases (chemically induced)
• Humans
• Lung Neoplasms (blood, drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Quinazolines (administration & dosage, adverse effects, blood)
• Treatment Outcome
• Gemcitabine