Abstract CT115: Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients
Authors: Pandha Hardev , Harrington Kevin , Ralph Cristy , Melcher Alan , Gupta Sumati , Akerley Wallace , Sandborn Rachael E. , Rudin Charles , Rosenberg Jonathan , Kaufman David , Schmidt Emmett , Grose Mark , Shafren Darren R. 
Published: July 2017

Abstract
Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Tumor infection by CVA21 can increase levels of immune-checkpoint molecules, immune-cell infiltration and enhancement of systemic antitumor immune response. Preclinical studies in immune-competent mouse models of NSCLC and melanoma confirmed that combinations of IV CVA21 + anti-PD-1 mAbs mediated significantly greater antitumor activity compared to use of either agent alone. The combination of CVA21+pembrolizumab may translate to a potential benefit in the clinic. Interim data are presented on the Phase Ib study assessing safety and efficacy of IV CVA21 alone (Part A) and in combination with pembrolizumab (Part B) in advanced cancer pts.
Methods: The Phase I STORM: Systemic Treatment Of Resistant Malignancies: NCT02043665 (KEYNOTE-200): Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 alone and in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Treatment: Part A: Pts were infused with CVA21 in 100 mL saline in Cohort 1 (n = 3), at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = 10) at a dose of 1 x 109 TCID50 on study days 1,3,5,22 and Q3W for 6 additional infusions. Part B: Pts are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT.
Results: Part A: Enrolment is complete. IV delivery of CVA21 to all patients in Part A was generally well tolerated, with no Grade 3 or 4 product-related AE’s with a median of 6 CVA21 infusions per patient. CVA21 tumor targeting in patients with melanoma, NSCLC and bladder cancer patients in Cohort 3 was confirmed by detection of CVA21 viral RNA in tumor biopsies at study Day 8 and viral replication by IHC in melanoma tumor biopsies. Of the 13 patients from Cohorts 1-3 eligible for investigator best overall response assessment, 1 PR, 8 SD and 4 PD were observed. Part B: The combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with that of Cohort 3 currently underway. All patients in Part B have displayed active host-antiviral immune responses by developing detectable anti-CVA21 neutralizing antibodies by study Day 22.
Conclusions: Intravenous delivery of CVA21 is able to target metastatic tumor deposits with the potential to up-regulate PD-L1 expression during the viral replication process. Systemic administration of CVA21 alone or in combination with pembrolizumab has been generally well-tolerated with at present no DLT’s.
Citation Format: Hardev Pandha, Kevin Harrington, Cristy Ralph, Alan Melcher, Sumati Gupta, Wallace Akerley, Rachael E. Sandborn, Charles Rudin, Jonathan Rosenberg, David Kaufman, Emmett Schmidt, Mark Grose, Darren R. Shafren. Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients [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 CT115. doi:10.1158/1538-7445.AM2017-CT115