LAUSR

Background: Coxsackievirus A21 (CVA21) is a novel bio-selected oncolytic, immunotherapeutic agent. Intratumoral (i.t.) CVA21 injection can induce selective tumor-cell infection, immune-cell infiltration, IFN-γ response gene up-regulation, increased PD-L1 expression, tumor cell lysis and systemic anti-tumor immune responses. Preclinical studies in an immune-competent mouse model of melanoma have revealed that combinations of i.t. CVA21 and anti-PD-1 blockade mediate significantly greater antitumor activity compared to use of either agent alone. A clinical trial evaluating combination CVA21 and pembrolizumab in patients with melanoma was initiated and preliminary data on a pre-established futility endpoint are presented here. Materials and Methods: This is a single-arm, multi-institutional open-label phase Ib clinical trial of i.t. CVA21 and i.v. pembrolizumab for treated or untreated unresectable Stage IIIC-IVM1c melanoma. Subjects with injectable disease receive up to 3 x 10 8 TCID 50 CVA21 i.t. on Days 1, 3, 5, 8, and then every 3 weeks for up to 19 injections. Subjects also receive pembrolizumab (2mg/kg) i.v. every 3 weeks starting on Day 8. The primary endpoint is safety/tolerability by incidence of dose-limiting toxicity. Secondary endpoints include best ORR by immune-related response criteria, progression-free survival, overall survival, quality of life, changes in melanoma-specific T cells, PD-L1 expression and Th1/Th2 gene expression profiles. The protocol included a futility analysis after the first 12 patients. Results : To date, 14 subjects have started on protocol therapy. Overall, the adverse events have been low-grade constitutional symptoms related to CVA21 and expected pembrolizumab-related side effects. No DLT’s have been reported. Currently, 11 patients are evaluable for investigator response assessment, not including 2 subjects who have not yet reached their first assessment and 1 subject who left the study early due to an unrelated adverse event. Among the evaluable subjects, the ORR was 73% (8/11). The DCR (CR+PR+SD) is currently 91% (10/11). In subjects with stage IVM1c disease, the ORR and the DCR is 100% (5/5). The study has met its primary statistical futility endpoint of achieving ≥2 confirmed objective responses (CR or PR) in the first 12 patients enrolled. Currently, the median time to response is 1.6 months. One of the 8 responders displayed early pseudo-progression and later developed a partial response. Conclusions: At a pre-specified futility analysis, combination CVA21 and pembrolizumab appears to be well-tolerated. Early tumor monitoring has identified encouraging reductions in a number of injected and non-injected lesions. Based on these initial results, the sample size has now been expanded to enroll up to 50 patients. Combination therapy of CVA21 and pembrolizumab may represent a new approach for the treatment of patients with injectable advanced melanoma. Citation Format: Ann W. Silk, Howard Kaufman, Nashat Gabrail, Janice Mehnert, Jennifer Bryan, Jacqueline Norrell, Daniel Medina, Praveen Bommareddy, Darren Shafren, Mark Grose, Andrew Zloza. Phase 1b study of intratumoral Coxsackievirus A21 ( C V A 21) and systemic p emb r olizumab in a dvanced melanoma patients: Interim results of the CAPRA clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT026. doi:10.1158/1538-7445.AM2017-CT026