A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer

• Published in: Journal of pancreatic cancer 2021-03, Vol.7 (1), p.8-19
• Main Authors: Muscarella, Peter, Bekaii-Saab, Tanios, McIntyre, Kristi, Rosemurgy, Alexander, Ross, Sharona B, Richards, Donald A, Fisher, William E, Flynn, Patrick J, Mattson, Alicia, Coeshott, Claire, Roder, Heinrich, Roder, Joanna, Harrell, Frank E, Cohn, Allen, Rodell, Timothy C, Apelian, David
• Format: Article
• Language: English
• Subjects: Antigens; Cancer therapies; Drug dosages; Drug withdrawal; Enrollments; Immunotherapy; Mortality; Mutation; Original; Pancreas; Pancreatic cancer; Population; Proteins; Tumors
• ISSN: 2475-3246; 2475-3246
• DOI: 10.1089/pancan.2020.0021

GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected -mutated pancreas cancer. Subjects (  = 176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer. Immune responses were measured by interferon-γ (IFNγ) ELISpot assay and by regulatory T cell (Treg) frequencies on treatment. Pretreatment plasma was retrospectively analyzed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry for proteomic signatures predictive of GI-4000 responsiveness. GI-4000 was well tolerated, with comparable safety findings between treatment groups. The GI-4000 group showed a similar pattern of median recurrence-free and overall survival (OS) compared with placebo. For the prospectively defined and stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs. 56%), an improvement in OS (523.5 vs. 443.5 days [hazard ratio (HR) = 1.06 [confidence interval (CI): 0.53-2.13],  = 0.872), and increased frequency of immune responders (40% vs. 8%;  = 0.062) for GI-4000 versus placebo and a 159-day improvement in OS for R1 GI-4000 immune responders versus placebo (  = 0.810). For R0 resection subjects, no increases in IFNγ responses in GI-4000-treated subjects were observed. A higher frequency of R0/R1 subjects with a reduction in Tregs (CD4 /CD45RA /Foxp3 ) was observed in GI-4000-treated subjects versus placebo (  = 0.033). A proteomic signature was identified that predicted response to GI-4000/gemcitabine regardless of resection status. These results justify continued investigation of GI-4000 in studies stratified for likely responders or in combination with immune check-point inhibitors or other immunomodulators, which may provide optimal reactivation of antitumor immunity. ClinicalTrials.gov Number: NCT00300950.