Background: CAVATAKTM is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21). In a phase 2 study, intratumoral (i.t.) CVA21 injection of advanced melanoma lesions resulted in increases in tumor immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122 which may be a potential prognostic marker for enhanced anti-tumor activity by anti-CTLA-4 blockade strategies. Intratumoral replication of CAVATAK may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. We present the preliminary data of the open-label, Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of novel immunotherapy combination Coxsackievirus A21 and ipilimumab in patients (pts) with advanced melanoma.

Methods: The Phase Ib MITCI study (NCT02307149) is investigating the efficacy and safety of i.t. CVA21 and i.v. ipilimumab in up to 50 pts with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts received up to 3 x 108 TCID50 CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipilimumab (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. The first response assessment (irWHO) occurred at study Day 106. The primary endpoint was to assess safety of CVA21 in combination with ipilimumab treatment.

Results: At present no DLT’s have been reported in the 23 pts currently enrolled. Combination treatment has been generally well-tolerated with surprisingly only one Gr 3 or higher treatment-related AE being ipilimumab-related fatigue. The study met its primary statistical futility endpoint of achieving ≥ 4 confirmed objective responses (CR or PR) in the first 12 pts enrolled. Currently, of the first 18 pts eligible for investigator response assessment, the confirmed ORR for the ITT population is 50.0% (9/18), with the ORR for immune checkpoint-naïve pts being 60% (6/10) and previous immune checkpoint therapy pts being 38% (3/8). Of note, is the encouraging ORR of 57.1% (4/7 pts) in pts with stage IVm1c disease. The DCR (CR+PR+SD) on the ITT population is currently 78% (14/18) of which 66% of patients have been administered prior systemic therapy(s) with DCR of 100% (7/7) in pts with stage IVm1c disease. All responses were observed by 3.5 mths with complete tumor responses being observed in individual injected and non-injected lesions. Preliminary immune monitoring has indicated that CVA21 + ipilimumab increases the % of activated CD8 and CD4 T-cells with effector and memory phenotypes in the peripheral blood. The greatest increases in activated T cells in the peripheral blood occurred after the third ipilimumab dose.

Conclusions: Treatment of pts with CVA21 and ipilimumab has demonstrated durable response with minimal toxicity. The combination immunotherapy treatment has displayed anti-tumor activity in local, visceral and non-visceral lesions. The preliminary ORR rate for the ITT population of 50.0% is higher than published rates for either agent used alone (CVA21: ~28% and ipilimumab :~15-20%) in advanced melanoma patients. Finally, responses are observed in pts with PD following immune checkpoint inhibitor therapy, suggesting the additive therapeutic benefit of CVA21 with ipilimumab.

Citation Format: Brendan Curti, Jon Richards, Sigrun Hallmeyer, Mark Faries, Robert Andtbacka, Greg Daniels, Mark Grose, Darren R. Shafren. The MITCI (Phase 1b) study: A novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment [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 CT114. doi:10.1158/1538-7445.AM2017-CT114