Originally published as JCO Early Release 10.1200/JCO.2005.01.109 on October 3 2005
Journal of Clinical Oncology, Vol 23, No 35 (December 10), 2005: pp. 8968-8977
© 2005 American Society of Clinical Oncology.
Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206
Antoni Ribas,
Luis H. Camacho,
Gabriel Lopez-Berestein,
Dmitri Pavlov,
Cecile A. Bulanhagui,
Robert Millham,
Begoña Comin-Anduix,
James M. Reuben,
Elisabeth Seja,
Charla A. Parker,
Amarnath Sharma,
John A. Glaspy,
Jesus Gomez-Navarro
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
Address reprint requests to Luis H. Camacho, MD, MPH, Phase I Program/Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 422, Houston, TX 77030; e-mail: lhcamacho{at}mdanderson.org.
PURPOSE: Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.
PATIENTS AND METHODS: Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose.
RESULTS: Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response.
CONCLUSION: CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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