PMID- 24618589 OWN - NLM STAT- MEDLINE DCOM- 20150529 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 3 DP - 2014 TI - Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PG - e90353 LID - 10.1371/journal.pone.0090353 [doi] LID - e90353 AB - BACKGROUND: In advanced cancers, transforming growth factor-beta (TGFbeta) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFbeta monoclonal antibody that neutralizes all isoforms of TGFbeta. 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. FAU - Morris, John C AU - Morris JC AD - Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America. FAU - Tan, Antoinette R AU - Tan AR AD - Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America. FAU - Olencki, Thomas E AU - Olencki TE AD - Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America. FAU - Shapiro, Geoffrey I AU - Shapiro GI AD - Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. FAU - Dezube, Bruce J AU - Dezube BJ AD - Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America. FAU - Reiss, Michael AU - Reiss M AD - Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America. FAU - Hsu, Frank J AU - Hsu FJ AD - Genzyme Corporation, Cambridge, Massachusetts, United States of America. FAU - Berzofsky, Jay A AU - Berzofsky JA AD - Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America. FAU - Lawrence, Donald P AU - Lawrence DP AD - Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America. LA - eng SI - ClinicalTrials.gov/NCT00356460 GR - Intramural NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20140311 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Transforming Growth Factor beta) RN - 375142VBIA (fresolimumab) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/pharmacology/*therapeutic use MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Carcinoma, Renal Cell/diagnosis/*drug therapy/*pathology MH - Female MH - Humans MH - Kidney Neoplasms/diagnosis/*drug therapy/*pathology MH - Male MH - Melanoma/*drug therapy/*pathology MH - Middle Aged MH - Neoplasm Staging MH - Positron-Emission Tomography MH - Tomography, X-Ray Computed MH - Transforming Growth Factor beta/antagonists & inhibitors/blood MH - Treatment Outcome PMC - PMC3949712 COIS- Competing Interests: The authors have the following interests: FJ Hsu was an employee of Genzyme Corporation. JA Berzofsky received research support from Genzyme Corporation, and M Reiss was a consultant on Advisory Boards for Genzyme Corporation. This work was partly supported by Genzyme Corporation who also provided the investigational agent GC1008. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. EDAT- 2014/03/13 06:00 MHDA- 2015/05/30 06:00 PMCR- 2014/03/11 CRDT- 2014/03/13 06:00 PHST- 2013/09/21 00:00 [received] PHST- 2014/01/26 00:00 [accepted] PHST- 2014/03/13 06:00 [entrez] PHST- 2014/03/13 06:00 [pubmed] PHST- 2015/05/30 06:00 [medline] PHST- 2014/03/11 00:00 [pmc-release] AID - PONE-D-13-39360 [pii] AID - 10.1371/journal.pone.0090353 [doi] PST - epublish SO - PLoS One. 2014 Mar 11;9(3):e90353. doi: 10.1371/journal.pone.0090353. eCollection 2014.