Originally published as JCO Early Release 10.1200/JCO.2008.19.2435 on January 12 2009

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Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; H Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Pittsburgh School of Medicine, Pittsburgh, PA; University of Chicago, Chicago, IL; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Pfizer Global Research & Development, New London, CT; University of California Los Angeles, Los Angeles, CA.

Corresponding author: Luis H. Camacho, MD, MPH, Oncology Consultants, Department of Research, 920 Frostwood, Ste 780, Houston, TX 77024; e-mail: lcamacho{at}oncologyconsultants.com.

Purpose Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.

Patients and Methods Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months.

Results No dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm).

Conclusion Multiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

Supported by Pfizer Inc (study support and medical editorial assistance).

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; and at the 11th World Congress on Cancers of the Skin, June 8-11, 2007, Amsterdam, Netherlands.

Clinical Trials Registration Number: NCT00086489; url: http://clinicaltrials.gov/ct2/show/NCT00086489.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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