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.
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
F A L M
FA
Eskens
Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.
P
P
Tresca
Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.
D
D
Tosi
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
L
L
Van Doorn
Oncology Division and Trial Operations Department, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.
H
H
Fontaine
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
A
A
Van der Gaast
Division of Drug Disposition DSAR, Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France.
C
C
Veyrat-Follet
Oncology Division and Trial Operations Department, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.
C
C
Oprea
Division of Biostatistics & Programming, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.
M
M
Hospitel
Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.
V
V
Dieras
D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012694:Serine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D012694:Serine; C400245:AC 7700