Background: Triple negative breast cancer (TNBC) is an aggressive subtype accounting for 15% of all breast cancer cases. It is characterized by larger tumor size, higher grade, early peak of recurrence, and a worse 5-year overall survival rate compared to other breast cancer subtypes. Chemotherapy serves as the backbone for the treatment of metastatic TNBC. Treatment with immunotherapy in combination with Abraxane, a taxane-based chemotherapy, is of benefit only in PD-L1 positive tumors, which represents a minority of the patients. Pelareorep, a proprietary isolate of the unmodified, replication competent reovirus type 3 Dearing (T3D), has been shown to upregulate PD-L1 expression in tumor and inflammatory cells and downregulate intra-tumoral regulatory T-cells in the tumor microenvironment in pre-clinical and early clinical studies. Retifanlimab is a PD-1 inhibitor currently in development. The rationale for this clinical study is that the administration of pelareorep will prime the tumor microenvironment for enhanced tumor response to PD-1 inhibitor retifanlimab.Trial design: This is a phase II multi-site single-arm clinical trial to study the combination of PD-1 inhibitor retifanlimab and the oncolytic virus Pelareorep in metastatic triple negative breast cancer who have progressed on chemotherapy. Eligible patients will receive pelareorep 4.5x1010 TCID50 /day IV, on Days 1, 2, 15 and 16 and retifanlimab 500mg IV on day 3 of every 28-day cycle until disease progression or unacceptable toxicity. Patient will be monitored clinically and radiologically for response to treatment. Tumor tissue, stool and blood samples will be collected while on treatment to evaluate changes in PD-L1 expression, gut microbiome and inflammatory cells induced by the study drugs. (ClinicalTrials.gov Identifier: NCT04445844) Eligibility criteria: Eligible patients will include premenopausal/postmenopausal women with metastatic TNBC who have previously received 1-2 prior lines of chemotherapy in the metastatic setting. ECOG PFS 0-2. Specific aims: Primary endpoint will be objective response rate (ORR) and safety, determined by the number, frequency, duration, and severity of AEs using CTCAE v5.0. The secondary end-points will be progression free survival (PFS), overall survival (OS) and duration of response (DOR) and quality of life measures using EORTC QLQ-C30. Statistical methods: Simon’s optimal 2-stage design will be used to calculate sample size. In the first stage, 14 patients will be accrued. If there are 1 or fewer responses in these 14 patients, the study will be stopped. Otherwise, 11 additional patients will be accrued for a total of 25. The null hypothesis will be rejected if 4 or more responses are observed in 25 patients. The first 6 patients will be enrolled in a staggering interval for the safety run-in phase of the study. Accrual: The study will enroll up to 25 patients at Rutgers Cancer Institute of New Jersey and Ohio State University Comprehensive Cancer Center Contact information: Mridula George, MD Email: mridula@cinj.rutgers.edu

Citation Format: Mridula George, Nicole Williams, Maryam Lustberg, Coral Omene, Nancy Chan, Nisha Ohri, Maria Kowzun, Lindsay Potdevin, Firas Eladoumikdachi, Shicha Kumar, Robert Wesolowski, Grey Wilkinson, Danielle Tang, Sinae Kim, Shridar Ganesan, Bruce Haffty, Deborah Toppmeyer. Irene study: Phase 2 study of incmga00012 (retifanlimab)and the oncolytic virus pelareorep in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-32-02.