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Background: Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4) is a T lymphocyte receptor responsible for negative regulation of cellular immune responses. CTLA4 blockade with CP-675,206 may break peripheral immunological tolerance and induce anti-tumor activity. Methods: We studied the safety, pharmacokinetics (PK), immune properties, and clinical activity of CP-675,206 in 39 pts with measurable disease (34) and no evidence of disease (5) (melanoma 34; renal cell 4; colon 1) after a single IV infusion at one of 7 dose levels: 0.01 (3 pts), 0.1 (3), 1.0 (3), 3.0 (8), 6.0 (5), 10.0 (11), and 15 mg/kg (6). Five pts at the lowest dose cohorts were re-enrolled at a higher dose level, for a total of 44 administered doses. Results: Therapy was delivered as planned. CP-675,206 proved safe and overall was well tolerated. Common adverse events included dermatitis (17, 39%), fatigue (17, 39%), pruritus (11, 25%), and diarrhea (11, 25%). DLTs were G3 diarrhea (1 at 6 mg/kg; 3 at 15 mg/kg) and G3 dermatitis (1 at 15mg/kg). The single dose MTD is 10 mg/kg. All observed autoimmunity except vitiligo (asthma, dermatitis, diarrhea, hypophysitis, and hyperthyroidism) was manageable and reversible. Plasma CP-675,206 concentrations were measured by ELISA. Peak concentrations and systemic exposure increase with dose. Concentrations remain >10 μg/mL (target efficacious concentration) for >4 weeks at doses ≥6 mg/kg; t_½ is 25.6 days. Immune activation was assessed in a whole blood assay determining secreted IL-2 levels in response to Staphylococcal Enterotoxin A (SEA). CP-675,206 administration increased mean SEA reactivity 1-hr post-dose at all dose levels with a dose-response trend (P < 0.03). There were 2 CRs (18+, 8+ mo), 1 PR, and 6 SDs (3+ to 16 mo) among 34 pts with measurable disease. Conclusions: CTLA4 blockade can be induced with a single injection of CP-675,206. Related autoimmunity is reversible. Observed anti-tumor activity may be associated with breaking peripheral tolerance through this mechanism.

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