O-0002 A Phase 2 Adjuvant Trial of GI-4000 Plus Gemcitabine vs. Gemcitabine Alone in Ras+ Patients with Resected Pancreas Cancer: R1 Subgroup Analysis

ABSTRACT Introduction Patients with resected pancreas cancer treated with standard of care gemcitabine have a median overall survival of 22 months (vs 20 months with observation). Activating mutations in ras occur in > 90% of pancreas cancer cases. GI-4000 is a proprietary immunotherapy designed to target cells with activating ras mutations using whole, heat-killed recombinant Saccharomyces cerevisiae yeast (called Tarmogens = Tar geted Mo lecular Immuno gens ). Tarmogens have demonstrated selective killing of target cells expressing a number of cancer antigens including mutated Ras in vivo by activating an antigen-specific T cell mediated response. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus gemcitabine in patients with Ras mutant positive resected pancreas cancer. Methods The study enrolled 176 subjects with Ras mutant positive adenocarcinoma of the pancreas post resection randomized 1:1 to GI-4000 plus gemcitabine or placebo plus gemcitabine (stratified by resection status; R0 or R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of gemcitabine 1000 mg/m2 iv (day 1, 8, 15 every 28 days). Monthly GI-4000 or placebo were administered on the gemcitabine off-weeks and continued monthly until disease recurrence, intolerable toxicity, or death. The primary endpoint is recurrence-free survival. Data for the 39 R1 subjects (GI-4000 N = 19, Placebo N = 20) have been unblinded and analyzed. Results The GI-4000 group had an 11.4 week advantage in median overall survival (524 days vs 444 days), 16% advantage in 1 year survival (72% vs 56%), and a 4.6 week advantage in median RFS (287 days vs 255 days). The GI-4000 group showed a significantly higher rate of mutation specific T cell response to Ras by ELISpot assay; 7/15 (47%) vs 1/12 (8%), p = 0.032,with a more pronounced survival benefit in GI-4000 treated immune responders; 21.7 week advantage in median survival (596 Days vs 444 Days) compared to placebo. No significant novel toxicities have been observed to date. Conclusion GI-4000 in combination with adjuvant gemcitabine showed a clinically meaningful point estimate for the treatment effect on survival in R1 subjects with Ras mutant positive adenocarcinoma of the pancreas. GI-4000 was immunogenic and well tolerated. Ras specific immune response was associated with a more pronounced benefit in median survival. These data warrant further study in a definitively powered clinical trial for GI-4000 in the adjuvant setting in R1 subjects. The results for the R0 cohort will be reported when the data are mature.