title: Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  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/m(2) with two chemotherapy doublets; OCD, 75 mg/m(2) cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m(2) docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m(2) (cohort 3) or 200 mg/m(2) (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/m(2)). 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/m(2) ombrabulin with 75 mg/m(2) cisplatin/75 mg/m(2) docetaxel or 200 mg/m(2) paclitaxel/AUC6 carboplatin, every 3 weeks.
authors.affiliation: Drug Development Department (DITEP), University Paris Sud, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Gianluca
authors.initials: G
authors.lastname: Del Conte
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capri
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Corina
authors.initials: C
authors.lastname: Oprea
authors.forename: Byzance
authors.initials: B
authors.lastname: Daglish
authors.forename: Marie
authors.initials: M
authors.lastname: Hospitel
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077143:Docetaxel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D066066:Response Evaluation Criteria in Solid Tumors; D012694:Serine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D012694:Serine; D016190:Carboplatin; C400245:AC 7700; D017239:Paclitaxel; D002945:Cisplatin