Abstract CT026: Phase 1b study of intratumoral Coxsackievirus A21 (<i> <u>C</u> </i>V<i> <u>A</u> </i>21) and systemic <i> <u>p</u> </i>emb<i> <u>r</u> </i>olizumab in <i> <u>a</u> </i>dvanced melanoma patients: Interim results of the CAPRA clinical trial
Authors: Ann W. Silk, Howard Kaufman, Nashat Gabrail, Janice Mehnert, Jennifer Bryan, Jacqueline Norrell, Daniel Medina, Praveen Bommareddy, Darren Shafren, Mark Grose, Andrew Zloza
Journal: Cancer Research (2017)

Abstract 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 108 TCID50 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 (CVA21) and systemic pembrolizumab in advanced 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