The phase 1/2 GOBLET study's safety run-in results, presented at the 2025 Gastrointestinal Cancers Symposium, indicate that pelareorep combined with modified FOLFIRINOX (mFOLFIRINOX), with or without atezolizumab, demonstrates an acceptable safety profile in patients with newly diagnosed metastatic pancreatic ductal adenocarcinoma (PDAC). This suggests the potential for further exploration of this combination therapy in a challenging disease landscape.
The open-label, multiple-cohort GOBLET study is enrolling patients with confirmed metastatic PDAC who are candidates to receive mFOLFIRINOX. In the first stage, patients were randomized to receive pelareorep plus mFOLFIRINOX and atezolizumab (Arm A) or pelareorep plus mFOLFIRINOX (Arm B). Pelareorep is administered on days 1, 2, 8, 9, 15, and 16; mFOLFIRINOX is given on days 1 and 15; and atezolizumab is given on days 2 and 16 of each 28-day cycle.
Safety Profile
All nine patients in the safety run-in experienced at least one adverse event (AE), with seven experiencing grade 3 or higher AEs. Six patients experienced serious AEs, and three patients died after data cutoff; however, none of the deaths were determined to be treatment-related. The most common grade 3 or higher AEs were nausea (44.4%), increased γ-GGT (22.2%), and abdominal pain (22.2%). Serious AEs included nausea (22.2%), COVID-19 (20%), abdominal pain (11.1%), acute kidney injury (11.1%), and pulmonary embolism (11.1%).
According to lead study author Dr. Thomas Seufferlein, of the Department of Internal Medicine at Ulm University Hospital in Ulm, Germany, the observed AEs were consistent with the known safety profiles of the study drugs. An independent data safety monitoring board and the German regulatory authorities have approved the study to continue full enrollment, with ongoing monitoring of the combination therapies' safety.
Rationale for Combination
While immunotherapy has limited efficacy in the majority of metastatic PDAC patients, previous data suggest that the non-genetically modified reovirus pelareorep may have synergy with checkpoint inhibitors. Prior research indicated that pelareorep, when combined with nab-paclitaxel, gemcitabine, and atezolizumab, elicited responses in patients with metastatic PDAC.
The primary objectives of the GOBLET study include evaluating the safety and tolerability, as well as the objective response rates achieved with pelareorep plus mFOLFIRINOX with or without atezolizumab. Secondary objectives include progression-free survival, overall survival, survival rates at 12 and 24 months, duration of response, and disease control rate. Translational studies are also planned to evaluate tumor-infiltrating lymphocyte clonal expansion and other immunological changes.
Next Steps
Tumor response results to pelareorep plus mFOLFIRINOX with or without atezolizumab therapy are pending. Enrollment into cohort 5 of the GOBLET study will continue, and efficacy results will be reported when available.
