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|Ref Type||Journal Article|
|Authors||Cohn A, Morse MA, O'Neil B, Whiting S, Coeshott C, Ferraro J, Bellgrau D, Apelian D, Rodell TC|
|Title||Whole Recombinant Saccharomyces cerevisiae Yeast Expressing Ras Mutations as Treatment for Patients With Solid Tumors Bearing Ras Mutations: Results From a Phase 1 Trial.|
|Abstract Text||We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with advanced colorectal or pancreas cancer, was designed to evaluate safety, immunogenicity, response, and overall survival of ascending doses of the GI-4000 series of products, which express 3 different forms of mutated Ras proteins. The study enrolled 33 heavily pretreated subjects (14 with pancreas and 19 with colorectal cancer), whose tumors were genotyped before enrollment to identify the specific ras mutation and thereby to identify which GI-4000 product to administer. No dose limiting toxicities were observed and no subject discontinued treatment due to a GI-4000 related adverse event (AE). The majority of AEs and all fatal events were due to underlying disease progression and AE frequencies were not significantly different among dose groups. GI-4000 was immunogenic, as Ras mutation-specific immune responses were detected on treatment in ∼60% of subjects. No objective tumor responses were observed but based on imaging, clinical status and/or biochemical markers, stable disease was observed in 6 subjects (18%) on day 29, while 1 subject had stable disease at days 57 and 85 follow-up visits. The median overall survival was 3.3 months (95% confidence interval, 2.3-5.3 mo), and 5 subjects survived past the 48-week follow-up period. No significant dose-dependent trends for survival were observed. This first clinical trial in humans with GI-4000 demonstrated a favorable safety profile and immunogenicity in the majority of subjects.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|GI-4000||GI 4000|GI4000||RAS Inhibitor (Pan) 9||GI-4000 vaccine elicits an immune response by stimulating a specific cytotoxic T-cell response against the mutated forms of Ras (PMID: 29528991).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|NRAS G12D||colorectal cancer||predicted - sensitive||GI-4000||Phase I||Actionable||In a Phase I trial, GI-4000 was well tolerated, induced immune response in 61.3% (19/31) of evaluable subjects, and resulted in stable disease as best response in 18% (6/33) of patients with advanced pancreatic or colorectal cancer harboring KRAS mutations, including KRAS G12C (n=3), KRAS G12D (n=6), KRAS G12V (n=8), KRAS Q61L (n=1), and NRAS G12D (n=1) in patients with colorectal cancer (PMID: 29528991).||29528991|