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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1188-1196
Number of pages9
JournalInvestigational New Drugs
Volume32
Issue number6
DOIs
Publication statusPublished - Dec 1 2014

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Keywords

  • Chemotherapy
  • Ombrabulin
  • Platinum
  • Taxane
  • Vascular disrupting agent

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology
  • Medicine(all)

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