Phase I and pharmacokinetic study of vatalanib plus capecitabine in patients with advanced cancer

Angiogenesis inhibition is now a proven therapeutic strategy in treatment of several solid tumors. Vatalanib is a potent inhibitor of all known vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. In view of the effectiveness of angiogenesis inhibitor therapy when combined with chemotherapy and the established role of capecitabine in treatment of colorectal and breast cancer, we undertook a phase I clinical trial of the combination of capecitabine and vatalanib with the goal of developing a combination oral regimen. The study objectives were to determine the maximally tolerated dose of vatalanib that could be safely administered daily with capecitabine given orally for 14 out of 21 days to patients with advanced cancer; to characterize the safety, tolerability, and pharmacokinetic profile of vatalanib given in combination with capecitabine; and to describe any pharmacokinetic interactions between the drugs. The study had an initial dose escalation phase followed by a dose expansion phase. During the dose escalation phase, cohorts of at least three patients each were treated with capecitabine and escalating doses of vatalanib until the maximally tolerated dose of vatalanib was determined. Vatalanib given continuously at a dose of 1,250 mg/day could be safely combined with capecitabine at a dose of 2,000 mg/m²/day given for 14 of 21 days. Dose-limiting toxicities of the combination included fatigue, hypertension, dizziness, and proteinuria. Vatalanib did not alter the pharmacokinetics of 5-FU, the active metabolite of capecitabine. Vatalanib and capecitabine can be safely combined without unexpected toxicities or significant pharmacokinetic interactions.