title: A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome.
abstract: BACKGROUND
  Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM).
  
  
  METHODS
  Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression.
  
  
  RESULTS
  Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009).
  
  
  CONCLUSIONS
  There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.
authors.affiliation: Developmental Therapeutics Program, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Mooney
authors.forename: Govardhanan
authors.initials: G
authors.lastname: Nagaiah
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Jay K
authors.initials: JK
authors.lastname: Wasman
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Cooney
authors.forename: Panos S
authors.initials: PS
authors.lastname: Savvides
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bokar
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: Susan M
authors.initials: SM
authors.lastname: Flick
authors.forename: Paul H
authors.initials: PH
authors.lastname: Hartman
authors.forename: Jose D
authors.initials: JD
authors.lastname: Ortiz
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Lavertu
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001632:Bibenzyls / Q000627:therapeutic use*; D019002:CD56 Antigen; D016190:Carboplatin / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage; D013267:Stilbenes; D017741:Survivors; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D019002:CD56 Antigen; C522918:NCAM1 protein, human; D019006:Neural Cell Adhesion Molecules; D009943:Organophosphorus Compounds; D013267:Stilbenes; D016190:Carboplatin; C058728:fosbretabulin; D017239:Paclitaxel