GI-4000 targets cancers with Ras mutations.
Ras Mutation
We estimate that Ras mutations are found in approximately 180,000 new cancer cases each year in the United States across a spectrum of tumor types, including pancreas, non-small cell lung cancer (NSCLC), colorectal, endometrial and ovarian cancers, as well as melanoma and multiple myeloma.
The mutated Ras protein causes a normal cell to become malignant by altering cell division pathways, resulting in the uncontrolled proliferation of malignant cells. Studies have shown that tumors with Ras mutations are generally less responsive than tumors with normal Ras to conventional chemotherapy as well as approved targeted agents. However, there are no approved products that are specifically directed towards Ras mutations.
GI-4000 for mutated-Ras mediated cancers
We believe that targeted reduction of cells containing Ras mutations could result in improved clinical outcomes for patients with a number of human cancers due to the role mutated Ras plays in tumor growth. We believe there are no treatments targeting mutated Ras in late-stage clinical trials and that GI-4000’s unique mechanism of action may allow targeting of these tumors.
GI-4000 is a series of four product versions; each version is a heat-inactivated S. cerevisiae yeast expressing a unique combination of three Ras mutations, collectively targeting seven of the most common Ras mutations observed in human cancers. In the GI-4000 clinical trials, each patient’s tumor is sequenced to identify the specific Ras mutation contained in the patient’s tumor and the corresponding, off-the-shelf Tarmogen containing the identified mutated protein is then administered. Each Tarmogen in the GI-4000 series is manufactured and vialed separately.
Clinical Program
Pancreas Cancer
We are developing GI-4000 in patients with resected pancreas cancer in combination with gemcitabine. GI-4000-02 is a fully-enrolled Phase 2b, randomized, double-blind, placebo-controlled, multi-center, adjuvant clinical trial of GI-4000 plus gemcitabine or placebo plus gemcitabine in patients with R0 or R1 resected pancreas cancer. The primary endpoint for this clinical trial is recurrence-free survival. Secondary endpoints include overall survival, immune responses and biomarkers of disease burden.
Following resection, subjects were prospectively stratified into two groups by resection status and both the R1 and R0 groups were randomly assigned into two treatment groups at a one-to-one ratio to receive either 40YU of GI-4000 plus gemcitabine or placebo plus gemcitabine. An R0 resection is defined by the absence of microscopic residual disease at the surgical margin. An R1 resection is defined by the presence of microscopic residual disease at the surgical margin. R0 and R1 patients have different expected survival rates, with R0 patients living longer on average.
In the R1 group, we observed the following:
- A 2.6 month advantage in median overall survival for the 19 subjects in the GI-4000 group compared to the 20 subjects in the placebo group (17.2 months compared to 14.6 months, respectively), representing an 18% relative advantage;
- Of subjects tested for immune response, 7 of 15 subjects in the GI-4000 group showed Ras mutation specific T cell response compared to 1 of 12 subjects in the placebo group;
- A 5.0 month improvement in median overall survival for GI-4000 immune responders compared to the 20 subjects in the placebo group (19.6 months compared to 14.6 months), representing a 34% relative improvement;
- A 16% advantage in one-year survival for subjects in the GI-4000 group (72% compared to 56% in the placebo group) representing a 30% relative improvement;
- A one month advantage in median recurrence free survival for the 19 subjects in the GI-4000 group compared to the 20 subjects in the placebo group (9.6 months compared to 8.5 months, respectively, representing a 13% relative advantage);
- A safety profile for GI-4000 treated subjects consistent with what is generally observed in patients with early stage resected pancreas cancer treated with gemcitabine alone, as determined by the Data Safety Monitoring Board; and
- This study was not powered to achieve statistical significance, and the improvement in survival and recurrence was not statistically significant.
Preliminary Proteomic Analysis of GI-4000-02
Proteomic analysis is a testing method intended to measure the levels of specific proteins in blood or other body fluid. The intent of this type of analysis is to identify a pattern of proteins in a patient’s blood which predicts a patient’s response to a treatment. An exploratory proteomic analysis, not specified in the original trial protocol, revealed a pattern of several specific proteins that appear to predict whether a subject treated with GI-4000 in the trial would have recurrence of their cancer relatively earlier or later. When these proteins were used to evaluate recurrence and overall survival after the trial, subjects with the specific protein signature that received GI-4000 appeared to have improved time to recurrence and overall survival compared to placebo treated subjects with the same specific protein signature. This protein signature was seen in 16/44 GI-4000 treated subjects reviewed, and 26/46 of the placebo group subjects, totaling 42/90 overall. This specific protein pattern must be prospectively validated in another clinical trial. If the protein pattern is validated, it could be used to select the most appropriate patients in future trials.
Non-Small Cell Lung Cancer (NSCLC) and Colon Cancer
GI-4000 is currently being investigated in two investigator-sponsored Phase 2a clinical trials in non-small cell lung cancer (NSCLC) and colon cancer.
GI-4000-03 is a single arm, open label, Phase 2a clinical trial in 24 subjects at Memorial Sloan Kettering Cancer Center (MSKCC) designed to evaluate GI-4000 following successful first-line treatment for non-metastatic, or Stage I to III, Ras-mutated NSCLC. Twenty-four subjects receive GI-4000 given in three weekly doses, followed by six monthly doses, followed by supplemental doses every three months for up to three years. The objectives for the study are to evaluate immune response and safety. The study is also evaluating recurrence-free survival and overall survival. The study met its primary efficacy endpoint with 50% of the GI-4000 treated subjects showing Ras-specific T cell responses
GI-4000-05 is a single center, open label, pilot Phase 2a clinical trial at the Lombardi Cancer Center at Georgetown University designed to evaluate GI-4000 in combination with first-line treatment in subjects with metastatic, or Stage IV, colorectal cancer with Ras mutations. Subjects receive GI-4000 in combination with chemotherapy plus bevacizumab. The objectives of this study are to evaluate safety, immune response, progression-free survival and overall survival. The study is being funded by Georgetown University, and we are supplying study drug.