P-49 GOBLET: A phase 1/2 multiple indication signal finding and biomarker study in advanced gastrointestinal cancers treated with pelareorep and atezolizumab – safety and preliminary response results

In GI cancers, checkpoint inhibitors are only effective in patients with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) tumors. Oncolytic viruses may improve the susceptibility of microsatellite stable (MSS) tumors to immunotherapy by modifying the tumor microenvironment (TME). Pelareorep (pela) is an intravenously delivered, non-genetically modified, oncolytic reovirus that mediates cancer cell killing by activating innate and adaptive immune responses directed against the tumor as well as direct tumor oncolysis. Accordingly, treatment with pelareorep results in increased T cell infiltration and PD-L1 expression in tumors which primes the TME for responsiveness to checkpoint inhibitors. Pela has demonstrated activity in many cancers including colorectal and pancreatic cancer. The GOBLET study is designed to assess the efficacy of pela plus atezolizumab (atezo) with or without chemotherapy in multiple GI cancers. GOBLET is a phase 1/2, open-label, non-randomized study in patients with advanced or metastatic GI cancers and utilizes a Simon two-stage design. In the first stage of the study, four treatment groups are being enrolled: Cohort 1 – First-line metastatic/advanced pancreatic cancer treated with pela plus atezo and chemotherapy (gemcitabine and nab-paclitaxel) (N=12); Cohort 2 – First-line MSI-H/dMMR metastatic CRC treated with pela plus atezo (N=19); Cohort 3 – Third-line metastatic CRC treated with pela plus atezo and chemotherapy (trifluridine/tipiracil) (N=14); and Cohort 4 – Second-line or later advanced squamous cell carcinoma of the anal canal treated with pela plus atezo (N=10). In Cohorts 1 and 3 (chemotherapy-containing cohorts) the first 3-6 patients enrolled comprise a safety run-in. The primary objectives of GOBLET are safety and efficacy measured by the objective response rate (ORR) at week 16. Based on pre-specified response thresholds, any cohort showing a positive ORR signal in Stage 1 may advance to the 2nd Stage and enroll additional patients. The three safety run-in patients in Cohorts 1 and 3 have been enrolled and their safety data reviewed by the independent Data Safety Monitoring Board (DSMB). The DSMB identified no safety signal and recommended that enrollment into these cohort continue without modification. Enrollment into Cohorts 2 and 4 is ongoing as these cohorts do not include safety run-ins. Tumor response results to date indicate that two of the three Cohort 1 patients had a partial response at week 8, the third Cohort 1 patient had a partial response at week 16. No safety signal was observed in either the Cohort 1 (first-line pancreatic cancer) or Cohort 3 (third-line CRC) patients. This is consistent with the favorable safety profile observed in prior studies of pela in multiple cancer indications, and it supports the ability to safely treat patients with advanced GI cancers using pela in combination with checkpoint inhibitors and chemotherapy. Preliminary tumor responses to therapy in first-line pancreatic cancer patients are encouraging.