title: Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.
abstract: OBJECTIVE
  The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.
  
  
  METHODS
  Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.
  
  
  RESULTS
  Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients.
  
  
  CONCLUSIONS
  The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. cristiana.sessa@eoc.ch
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorusso
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Françoise
authors.initials: F
authors.lastname: Farace
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lassau
authors.forename: Angelo
authors.initials: A
authors.lastname: Delmonte
authors.forename: Antonio
authors.initials: A
authors.lastname: Braghetti
authors.forename: Rastislav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Patrick
authors.initials: P
authors.lastname: Cohen
authors.forename: Marie
authors.initials: M
authors.lastname: Hospitel
authors.forename: Christine
authors.initials: C
authors.lastname: Veyrat-Follet
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012694:Serine; C400245:AC 7700