title: Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma.
abstract: BACKGROUND
  In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.
  
  
  METHODS
  In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.
  
  
  RESULTS
  Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks).
  
  
  CONCLUSIONS
  GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00356460.
authors.affiliation: Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Tan
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Olencki
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.affiliation: Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Reiss
authors.affiliation: Genzyme Corporation, Cambridge, Massachusetts, United States of America.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Hsu
authors.affiliation: Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; C560928:fresolimumab