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

F A L M Eskens, P Tresca, D Tosi, L Van Doorn, H Fontaine, A Van der Gaast, C Veyrat-Follet, C Oprea, M Hospitel, V Dieras, F A L M Eskens, P Tresca, D Tosi, L Van Doorn, H Fontaine, A Van der Gaast, C Veyrat-Follet, C Oprea, M Hospitel, V Dieras

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01907685.

Figures

Figure 1
Figure 1
Concentration-time profiles of ombrabulin, its active metabolite RPR258063 and docetaxel. Plasma concentrations in cycle 1 are shown for (A) ombrabulin and (B) RPR258063 by dose level according to median concentrations (N=57), and for docetaxel (C) 75 mg m−2 (N=38) and (D) 100 mg m−2 (N=18) presenting individual results against predicted values for a patient with a body surface area of 1.76 m2 and 1.89 m2, respectively.

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