Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer.

PURPOSE: Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer. PATIENTS AND METHODS: A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status or= 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months). CONCLUSION: Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.

Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells.

PURPOSE: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer. EXPERIMENTAL DESIGN: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics. RESULTS: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for >or=12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells. CONCLUSIONS: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade.