A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck

SU5416 is a novel small organic molecule that non-competitively inhibits the phosphorylation of the VEGF tyrosine kinase receptor, Flk-1. This phase IB study was performed to determine the safety, pharmacokinetics, and preliminary efficacy of the combination of SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck. Enrolled in the study were 12 patients with biopsy-proven recurrent or metastatic carcinoma of the head and neck. Six patients received intravenous SU5416 110 mg/m2 on days 1, 15, 18, 22 and 25, and paclitaxel 70 mg/m2 on days 8, 15 and 22. Since two patients experienced a dose-limiting toxicity (DLT) in cohort 1, the next six patients received identical treatment as above except the paclitaxel dose was reduced to 55 mg/m2 per week. A total of 42 cycles at two different dose levels were given. In cohort 1 there were two deep venous thromboses that were DLTs. In the second cohort there was a DLT consisting of a transient ischemic attack after receiving SU5416. Most of the other toxicities seen were grade 1 or 2 in nature and consisted of headache, facial flushing, and fatigue. Two patients developed extensive ulcerative cavities at sites of prior radiation. There were no significant changes in the pharmacokinetic parameters of SU5416 given with paclitaxel. Four patients had prolonged freedom from progression of 18, 28, 42, and 60 weeks duration. The combination of SU5416 with paclitaxel had a higher than expected incidence of thromboembolic events and prophylactic anticoagulation should be considered for future trials that combine an angiogenesis inhibitor with cytotoxic chemotherapy. Although the future development of SU5416 as a chemotherapeutic agent is unclear, there was a clinical benefit seen with this combination in 36% of the patients. This trial supports the use of developing antiangiogenic combinations, using molecular targeted agents, in head and neck carcinoma.