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PLoS One. 2014 Mar 11;9(3):e90353. doi: 10.1371/journal.pone.0090353. eCollection 2014.

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.

Author information

  • 1Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
  • 2Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
  • 3Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • 4Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 5Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
  • 6Genzyme Corporation, Cambridge, Massachusetts, United States of America.
  • 7Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

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.

TRIAL REGISTRATION:

Clinicaltrials.gov NCT00356460.

PMID:
24618589
[PubMed - indexed for MEDLINE]
PMCID:
PMC3949712
Free PMC Article
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