A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

BACKGROUND: The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours. METHODS: Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(−2) with 75 mg m(−2) docetaxel, then from 30 to 35 mg m(−2) with 100 mg m(−2) docetaxel. Recommended phase II dose cohorts were expanded. RESULTS: Fifty-eight patients were treated. Recommended phase II doses were 35 mg m(−2) ombrabulin with 75 mg m(−2) docetaxel (35/75 mg m(−2); 13 patients) and 30 mg m(−2) ombrabulin with 100 mg m(−2) docetaxel (30/100 mg m(−2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(−2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(−2) ombrabulin), eight lasting >3 months. CONCLUSIONS: Sequential administration of ombrabulin with 75 or 100 mg m(−2) docetaxel every 3 weeks is feasible.