Phase Ib study of intratumoral oncolytic coxsackievirus A21 (CVA21) and pembrolizumab in subjects with advanced melanoma

Background

Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody that has demonstrated overall and durable response rates in advanced melanoma patients, although less than half of treated patients respond. Therapeutic responses have been associated with tumor expression of PD-L1. Oncolytic viruses are live viral particles that can be injected into tumors resulting in lysis of tumor cells, release of tumor-associated antigens and increased expression of PD-L1. Coxsackievirus A21 (CVA21) is a native oncolytic virus that in phase I and II studies has been safe and well-tolerated with an overall response rate of 28.1% and a 1-year survival rate of 73.7% (Andtbacka et al). We hypothesize that combination CVA21 and pembrolizumab will be safe and well-tolerated, and result in improved clinical efficacy through increased expression of PD-L1 following virus therapy.

Trial design

In this phase I trial (NCT02565992), we will enroll 30 patients with advanced melanoma with at least one tumor deposit accessible for injection. The primary endpoint is the safety of CVA21 with pembrolizumab with secondary endpoints of overall response rate, progression-free and overall survival. Correlates include measures of T-cell subsets and antibody responses to melanoma antigens in tumor tissue and peripheral blood. Pre- and post-treatment tumor PD-L1 expression will be assessed and correlated with clinical benefit. Patients will receive up to 4.0 mL of intratumoral CVA21 on days 1, 3, 5, and 8 every 3 weeks for a maximum of 19 total injections, and pembrolizumab 2mg/kg IV every 3 weeks starting on day 8 for up to 2 years. Patients will be evaluated for toxicities until the dose-limiting toxicity (DLT) of CVA21 is reached, and for response by modified WHO criteria. Peripheral blood mononuclear cells will be collected at baseline, prior to pembrolizumab administration, and at study termination, and optional tumor biopsies will be obtained at baseline and at periodic intervals thereafter. The trial is currently screening eligible subjects.

Clinical trial identification

NCT02565992

Legal entity responsible for the study

Viralytics, Limited

Funding

Viralytics, Limited

Disclosure

H.L. Kaufman: Advisory boards for Amgen, EMD Serono, Merck, Prometheus and Sanofi. Speaker's bureau for Merck but returns all honoraria to Rutgers University. M. Grose, D. Shafren: Employee of Viralytics. All other authors have declared no conflicts of interest.