A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours
Mené sur 58 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I en escalade de dose évalue la dose maximale tolérée de l'ombrabuline en combinaison avec le docétaxel
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.