Abstract CT218: First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors
Authors: Purroy Noelia , Durham Nicholas , Phillips Marc , Hattersley Maureen M. , Jung Lindsey , Davar Diwakar , Zamarin Dmitriy , Johanns Tanner M. , Puzanov Igor 
Published: June 2022

Abstract
Background: Oncolytic viruses selectively infect tumors and activate antitumor immune responses via innate and adaptive pathways, leading to immunogenic cell death and potentiating the efficacy of immune checkpoint inhibitors. MEDI9253 is a recombinant Newcastle disease virus (NDV) that incorporates a human transgene encoding the immunostimulatory cytokine interleukin (IL)-12, which leads to tumor cell lysis and localized IL-12 expression. Preclinical studies show that MEDI9253 induces PD-L1 expression and recruits innate and adaptive immune cells to the tumor microenvironment (TME) and indicate that its antitumor activity is enhanced by concurrent PD-L1 blockade. This clinical study is evaluating intravenous (IV) MEDI9253 in combination with the anti-PD-L1 antibody durvalumab in patients with selected advanced solid tumors.
Methods: This is a phase I, multicenter, open-label, dose escalation and dose expansion trial (NCT04613492) enrolling patients with microsatellite-stable colorectal cancer (MSS-CRC), renal cell carcinoma (RCC) or melanoma. Eligibility criteria include progressed/refractory disease or intolerance to all prior lines of therapy with proven survival benefit for recurrent/metastatic disease. Patients must have life expectancy ≥12 weeks by GRIm score; histologically documented disease; adequate performance status (ECOG 0-1); adequate organ function; and presence of RECIST v1.1 measurable disease amenable to repeated biopsy. Exclusion criteria include untreated/uncontrolled metastatic CNS involvement. Patients must take precautions to prevent the theoretical risk of NDV transmission to humans and birds. The trial will enroll up to ~192 patients across 30 centers globally. The dose escalation phase will evaluate a single dose of IV MEDI9253 with sequential IV durvalumab, then multiple-dose cohorts of up to 4 ascending dose levels of MEDI9253 with sequential or concurrent durvalumab. The dose expansion phase will include 3 cohorts of ~20 patients, each enrolling a single tumor type. In both phases, durvalumab will be dosed for up to 2 years or until disease progression, clinical deterioration, withdrawal of consent or unacceptable toxicity. Pretreatment and on-treatment tumor biopsies are required for patients in multiple-dose cohorts. The primary objectives are evaluating the safety, tolerability and incidence of dose-limiting toxicities of MEDI9253 and identifying the optimal dose/schedule in combination with durvalumab. Secondary objectives include assessing initial efficacy (response and progression-free survival by RECIST v1.1, and overall survival), pharmacodynamics in the TME, immunogenicity, and pharmacokinetics (viremia and IL-12). The trial is recruiting.
Citation Format: Noelia Purroy, Nicholas Durham, Marc Phillips, Maureen M. Hattersley, Lindsey Jung, Diwakar Davar, Dmitriy Zamarin, Tanner M. Johanns, Igor Puzanov. First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT218.