title: Phase I/II trial of tremelimumab in patients with metastatic melanoma.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oncology Consultants, Department of Research, 920 Frostwood, Ste 780, Houston, TX 77024, USA. lcamacho@oncologyconsultants.com
authors.forename: Luis H
authors.initials: LH
authors.lastname: Camacho
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Bruce
authors.initials: B
authors.lastname: Redman
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pavlov
authors.forename: Cecile
authors.initials: C
authors.lastname: Bulanhagui
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Bozon
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomez-Navarro
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C520704:tremelimumab