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.

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.

Purpose: This phase II study assessed the antitumor activity of tremelimumab, a fully human, anti-CTL-associated antigen 4 monoclonal antibody, in patients with melanoma.Experimental Design: Patients with refractory/relapsed melanoma received 15 mg/kg tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive ≤4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety.Results: Of 251 patients enrolled, 246 (241 response-evaluable) received tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M 1c disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatmentrelated adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea (n = 28, 11%), fatigue (n = 6, 2%), and colitis (n = 9, 4%). There were 2 (0.8%) treatment-related deaths.Conclusions: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable ≥170 days since enrollment, suggesting a potential role for tremelimumab in melanoma.

Background: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.

Purpose: This phase II study assessed the antitumor activity of tremelimumab, a fully human, anti-CTL-associated antigen 4 monoclonal antibody, in patients with melanoma. Experimental Design: Patients with refractory/relapsed melanoma received 15 mg/kg tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive ≤4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety. Results: Of 251 patients enrolled, 246 (241 response-evaluable) received tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M 1c disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatmentrelated adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea (n = 28, 11%), fatigue (n = 6, 2%), and colitis (n = 9, 4%). There were 2 (0.8%) treatment-related deaths. Conclusions: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable ≥170 days since enrollment, suggesting a potential role for tremelimumab in melanoma.

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3000 Background: CP-675,206 has antitumor activity in pts with metastatic melanoma. A 2-stage, 2-arm phase II trial was conducted to choose the optimal dosing regimen for pivotal clinical trial testing. Methods: Eligible pts had measurable melanoma (stage IIIc or IV) progressing on or after prior therapy with ECOG PS = 1. In stage 1, 18 pts per arm were randomized to either 10 mg/kg monthly (10 Q1M) or 15 mg/kg every 3 months (15 Q3M). If 3 or more pts in either arm had CR or PR, then 25 more pts were entered to that arm. Primary endpoint was objective tumor response, and secondary endpoints were safety and survival. Results: 89 pts received at least 1 dose (44 at 10 Q1M, 45 at 15 Q3M), with both study arms moving to stage 2. 96% of pts had stage IV disease, and 57% had elevated LDH. There were no significant differences in age, sex, stage, or baseline LDH levels between study groups. A median of 3 doses (range, 1 to 26) at 10 Q1M and 1 dose (range, 1 to 9) at 15 Q3M were administered with 100% compliance. Dose delays occurred in 30% of pts treated at 10 Q1M and 16% at 15 Q3M. 2 pts at 10 Q1M and 5 pts at 15 Q3M continued on study beyond 12 months (mo). To date, 6 pts at 10 Q1M have been discontinued due to toxicity (3 diarrhea/colitis [1 requiring colectomy], Grave’s ophthalmopathy, pancreatitis, hypersensitivity reaction) and 2 pts at 15 Q3M (colitis and pancreatitis, diarrhea) (P = 0.14). There were no toxic deaths. 15 Q3M was associated with lower incidence of grade 3 or 4 AEs (31% vs 41% at 10 Q1M; P = 0.42). Responses by investigator assessment were 1 CR and 3 PRs at 10 Q1M, and 1 CR and 2 PRs at 15 mg/kg Q3M, including responses in skin, LN, bone, liver, lung, and adrenal glands. To date, only 1 pt with PR at 10 Q1M has relapsed, and the remaining responses are ongoing (18+ to 28+ mo). Median survival is 10.3 mo at 10 Q1M and 11.0 mo at 15 Q3M (P = NS). Conclusions: The 15 mg/kg Q3M regimen was chosen for further clinical testing based on comparable antitumor efficacy and a trend to improved feasibility and safety compared with 10 mg/kg Q1M. CP-675,206 at this dose and schedule is being examined in pivotal phase II and III clinical trials for pts with melanoma, and in early phase II trials in pts with CRC and NSCLC. No significant financial relationships to disclose.

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