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Investigational New Drugs
Published in: Investigational New Drugs 6/2014

01-12-2014 | PHASE I STUDIES

Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors

Authors: Rastislav Bahleda, Cristiana Sessa, Gianluca Del Conte, Luca Gianni, Giuseppe Capri, Andrea Varga, Corina Oprea, Byzance Daglish, Marie Hospitel, Jean-Charles Soria

Published in: Investigational New Drugs | Issue 6/2014

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Summary

Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3–4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.
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Metadata
Title
Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors
Authors
Rastislav Bahleda
Cristiana Sessa
Gianluca Del Conte
Luca Gianni
Giuseppe Capri
Andrea Varga
Corina Oprea
Byzance Daglish
Marie Hospitel
Jean-Charles Soria
Publication date
01-12-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 6/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0119-0

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