ABSTRACT
BACKGROUND: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4 monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted immune modulators that elicit durable single-agent antitumour activity in advanced cancer. METHODS: To determine the maximum tolerated dose (MTD) of these agents combined during this phase I study, patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg kg(-1)) every 12 weeks plus subcutaneous PF-3512676 (0.05, 0.10, or 0.15 mg kg(-1)) weekly. Primary end points were safety and tolerability; secondary end points included pharmacokinetics and antitumour activity. RESULTS: Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade ≥3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (≥170 days) partial response. No human antihuman antibody responses to tremelimumab were observed. CONCLUSION: Weekly PF-3512676 (≤0.15 mg kg(-1)) plus tremelimumab (≤10 mg kg(-1) every 12 weeks) was tolerable.
