Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA)

3007 Background: CD137 is a member of the TNFR family and functions as a costimulatory molecule. In preclinical studies BMS- 663513, a fully human anti-CD137 agonist monoclonal antibody provided costimulation to CD8+ and CD4+ T-cells, leading to enhanced IFNγ production, cytolytic activity, and increased survival. We conducted a first-in-human phase I dose-escalation study of BMS-663513 in pts with CA. Methods: BMS-663513 was administered IV every 3 weeks. In Part 1, the dose was escalated (0.3, 1, 3, 6, 10, and 15 mg/kg) in cohorts of 3–6 pts. In Part 2, pts with melanoma, RCC, and ovarian CA, 30 per CA, were stratified by tumor type and randomized to receive 1, 3, and 10 mg/kg dose levels. Tumor response (modified WHO) was determined after the 4th dose and then every 2 doses. After 4 doses, treatment continued in pts with antitumor activity and without dose-limiting toxicity (DLT). Tumor biopsies were obtained from pts in Part 1 pretreatment and during cycle 2; PBMC, serum, and plasma were also obtained from all pts at select times for exploratory biomarker analysis. Results: 83 pts (54 melanoma, 15 RCC, 13 ovarian and 1 prostate) have been treated. Part 2 melanoma enrollment is complete. In Part 1, single DLTs were reported in the 0.3 mg/kg (Gr 3 neutropenia), and 15 mg/kg (Gr 4 neutropenia) cohorts. Overall, fatigue (All, 26%, Gr 3–4, 3%), reversible Gr 3–4 transaminitis (11%) and Gr 3–4 neutropenia (5%) were the most common agent-related AEs. 3 PRs (18+ mo, 3+ mo, 1.5+ mo, all melanoma) and 4 SD (10 mo, 6 mo, 6 mo, 4+ mo) occurred at all three doses tested in expansion cohorts. Preliminary biomarker analysis demonstrated increased expression of IFN-inducible genes in peripheral blood, serum neopterin levels, and percentage of circulating activated (HLA-DR+, CD69+) CD8 and CD4 T-cells following a single treatment. Increased expression of CD8a and IFNγ were detected in post- treatment biopsies in a subset of pts. Conclusions: BMS-663513 was tolerable across a wide dose range (0.3–15 mg/kg). As a single agent, BMS-663513 demonstrates clinical activity that justifies its further evaluation both as a single agent and in combination with other treatment modalities. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb