Phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer: Clinical update on long term survival and biomarker correlates to overall survival.

Abstract

261 Background: In a phase 2a randomized study, metastatic pancreatic ductal adenocarcinoma (PDA) patients treated sequentially with two vaccine-based immunotherapies showed extended overall survival (OS) with tolerable side effects. Treatment included low-dose cyclophosphamide (CY) to inhibit T-regulatory cells prior to GVAX, an irradiated GM-CSF-secreting allogeneic PDA cell vaccine, which activates a broad antigenic response, followed by CRS-207, a live-attenuated, mesothelin-expressing Listeria monocytogenes vaccine which stimulates innate and adaptive immunity. Methods: Patients were enrolled with metastatic PDA who received or refused ≥1 prior chemotherapy, had ECOG ≤1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B). PBMC and serum were collected over the course of treatment for immune and biomarker analyses. CyTOF, ELISPOT, and luminex were used to identify biomarker correlates of OS. Results: We previously reported phase 2a results demonstrating median OS in patients treated in arm A was 6.1 months compared to 3.9 months for those in arm B (HR=0.54, one-sided p=0.011). As of August 2014, 8 patients are still alive (median time on study: 768 days; range: 596-880), with 3 subjects on combination treatment. Mesothelin-specific CD8+T cell responses following CY/GVAX correlated with improved OS in both arms. Elevated frequencies of T cell subsets and a panel of baseline serum cytokines also correlated with longer OS. Strikingly, hierarchical clustering based on expression of biomarkers showed significant clustering of patients according to OS. Conclusions: Treatment with CY/GVAX and CRS-207 was well-tolerated and resulted in improved OS compared to CY/GVAX alone. A larger phase 2b, 3-arm, randomized trial is ongoing and plans to treat 240 adults with previously-treated metastatic PDA with CY/GVAX and CRS-207, CRS-207 alone, or standard chemotherapy. Preliminary results using patients’ PBMCs and sera revealed potential biomarkers for OS. Clinical trial information: NCT01417000. Clinical trial information: NCT01417000.