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 42mgm(-2) with 75 mgm(-2) docetaxel, then from 30 to 35 mgm(-2) with 100 mgm(-2) docetaxel. Recommended phase II dose cohorts were expanded. Results: Fifty-eight patients were treated. Recommended phase II doses were 35 mgm(-2) ombrabulin with 75 mgm(-2) docetaxel (35/75 mgm(-2); 13 patients) and 30 mgm(-2) ombrabulin with 100 mgm(-2) docetaxel (30/100 mgm(-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 mgm(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mgm(-2) ombrabulin), eight lasting > 3 months. Conclusions: Sequential administration of ombrabulin with 75 or 100 mgm(-2) docetaxel every 3 weeks is feasible.