3046 Background: Tremelimumab, a fully human monoclonal antibody specific for cytotoxic T-lymphocyte antigen 4 (CTLA4), and PF-3512676, an oligodeoxynucleotide toll-like receptor 9 agonist, are both novel, targeted immune modulators that can elicit durable antitumor responses in patients with advanced cancer. The tolerability of the combination of these two agents was investigated.
METHODS
Eligibility criteria included advanced melanoma or other advanced cancer, ECOG performance status of 0 or 1, and no history of autoimmune disease. Patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg/kg) every 12 weeks plus 0.05 mg/kg subcutaneous PF-3512676 weekly. Further escalation of PF-3512676 (to 0.1 mg/kg and 0.2 mg/kg) was planned once the MTD of tremelimumab had been determined. Primary endpoint was safety of the treatment combination; secondary endpoints included clinical activity, pharmacokinetics (PK), and immunologic measurements.
RESULTS
To date, 15 patients (melanoma, n = 12; mesothelioma, n = 2; prostate, n = 1) have been treated in this study: 3 at dose level 1 (6 mg/kg tremelimumab + 0.05 mg/kg PF-3512676); 6 at dose level 2 (10 mg/kg tremelimumab + 0.05 mg/kg PF-351276); and 6 at dose level 3 (15 mg/kg tremelimumab + 0.05 mg/kg PF-3512676). There were two DLTs at dose level 3: G3 diarrhea (n=1) and G3 nausea and vomiting associated with biopsy-proven duodenitis (n=1). One DLT, G3 hypophysitis, occurred at dose level 2. Patients with DLTs responded to corticosteroid therapy. Common adverse events included mild to moderate PF-3512676 injection site reactions (n=14), mild to moderate flu-like symptoms (n=9), G1/2 diarrhea (n=9), and G1/2 nausea (n=8). Presently, there are 2 PRs (13%) and 5 SDs among the 15 patients. Updated safety, efficacy, and PK data will be reported.
CONCLUSIONS
At dose levels tested to date, the combination of tremelimumab and PF-3512676 has been tolerable and showed evidence of antitumor activity in patients with advanced melanoma. The MTD for this combination has yet to be determined, and a fourth intermediate dose level (10 mg/kg tremelimumab + 0.1 mg/kg PF-3512676) is currently being explored. [Table: see text].