Abstract CT021: Phase Ib study of a novel immunotherapy combination therapy of intralesional coxsackievirus A21 and systemic ipilimumab in patients with advanced melanoma
Authors: Curti Brendan , Richards Jon , Faries Mark , Grose Mark , Karpathy Roberta , Shafren Darren R. 
Published: July 2016

Abstract
Background: CVA21 (CAVATAK) is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21. Intratumoral (i.t.) CVA21 injection can induce preferential tumor cell infection, tumor immune-cell infiltration, up-regulation of γ-INF response genes, cell lysis and enhancement of a systemic anti-tumor immune response. Pre-clinical studies in an immune-competent mouse model of melanoma have revealed that combinations of intralesional CVA21 and anti-CTLA-4 or anti-PD-1 mAbs mediated significantly greater antitumor activity and compared to use of either agent alone. Presented are the interim data of the open-label, multicenter Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of novel immunotherapy combination Coxsackievirus A21 and ipilimumab in patients 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 26 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts received up to 3 × 10e8 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. Treatment is continued until DLT, intolerance, all injectable tumors disappeared, or confirmed disease progression (PD) per immune-related (ir) WHO response criteria. The first response assessment occurs at study Day 106. Key eligibility criteria were ? 18 yrs old, ECOG PS 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis ? 1.0 cm. The primary endpoint was to assess safety of CAVATAK in combination with scheduled ipilimumab treatment. Secondary endpoints included irWHO objective response rate (ORR), responses in injected and non-injected lesions, durable response rate (continuous response ? 6 mos), median time to initial response, survival and QOL.
Results: At present, of the 7 patients enrolled, no DLT's have been reported. Combination treatment has been generally well-tolerated with only 2 Gr 3 AEs reported, one with ipilimumab-related fatigue and the other with unrelated hypertension. Of 5 pts with investigator assessed response, ORR was 80%, with all responses occurring by 3.5 months and in both injected and non-injected lesions. Responses were observed in patients with Stage IIIC and Stage IV M1a/c disease. Response rates in individual injected and non-injected lesions were 80% (n = 10) and 87% (n = 15), respectively. Complete tumor responses were observed in some visceral and non-visceral lesions. Patients developed notable levels of anti-CVA21 serum neutralizing antibody by Day 22.
Conclusions: Intralesional CVA21 + ipilimumab is a promising novel oncolytic immunotherapeutic combination for the treatment of unresectable Stage IIIC-IVM1c melanoma. At present no DLT has been achieved, with no Gr 3/4 CVA21-related AEs observed. The preliminary overall response rate (80%) is higher than published rates for either agent used alone (CVA21: 28.1% and ipilimumab:∼15-20%) in advanced melanoma patients. The combination immunotherapy treatment is generally well tolerated and has displayed antitumor activity in both local and systemic disease, also within environments of high levels of anti-CVA21 serum neutralizing antibody.
Citation Format: Brendan Curti, Jon Richards, Mark Faries, Mark Grose, Roberta Karpathy, Darren R. Shafren. Phase Ib study of a novel immunotherapy combination therapy of intralesional coxsackievirus A21 and systemic ipilimumab in patients with advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT021.