GI-4000 / Mutated Ras


GI-4000 / Mutated Ras

Our GI-4000 product candidates are designed to stimulate immune responses against the mutated Ras protein, a protein that is implicated in difficult to treat cancers

We estimate that Ras mutations are found in approximately 200,000 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.

Studies have shown that tumors with Ras mutations may be generally less responsive than tumors with normal Ras to conventional chemotherapy as well as targeted agents. As a result, patients with Ras mutations have fewer available effective treatment options.

GI-4000 for mutated-Ras mediated cancers

We believe that targeted reduction of cells containing Ras mutations by the immune system 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 that GI-4000’s unique mechanism of action may allow targeting of these tumors.

GI-4000 is a product series of four Tarmogens; each Tarmogen is a different 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 administered. Each Tarmogen in the GI-4000 series is manufactured and vialed separately.

Clinical Program

Phase 2b — Pancreas Cancer

GI-4000 has been tested in subjects with resected pancreas cancer in combination with gemcitabine. We begin treating the patient when the overall tumor burden in the body is relatively low after resection, allowing enough time before disease progression for GI-4000 to induce an immune response against residual tumor.

We are developing GI-4000 in combination with gemcitabine as an adjuvant treatment in patients with resected pancreas cancer. We recently completed GI-4000-02 is a fully-enrolled Phase 2b, randomized, double-blind, placebo-controlled, multi-center, adjuvant clinical trial in 176 patients, with initial results reported in November 2012, evaluating GI-4000 plus gemcitabine or placebo plus gemcitabine in patients with R0 or R1 resected pancreas cancer. 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. The primary endpoint for this clinical trial was recurrence-free survival (RFS). Secondary endpoints include overall survival (OS), immune responses and biomarkers of disease burden, such as CA19-9 .


We performed a retrospective proteomic analysis of 90 pre-treatment blood samples remaining after all pre-specified analyses under the clinical trial protocol for GI-4000-02 were completed. The goal of the analysis was to identify a pre-treatment companion diagnostic test that could predict which subjects are likely to respond to treatment with GI-4000 regardless of their resection status to assist in subject selection for future clinical trials.

BDX-001, the resulting potential proteomic companion diagnostic test, appeared to predict whether a subject treated with GI-4000 and the chemotherapy drug gemcitabine in this trial would have improved recurrence free and overall survival compared to gemcitabine alone. We believe BDX-001 differentiates between subject blood samples using the relationship of 100 different proteins and protein fragments.

Overall, 21 of the 44 (48%) studied subject samples treated with GI-4000 and gemcitabine were classified as BDX-001 positive. In BDX-001 positive subject samples treated with GI-4000 and gemcitabine, there was an 11.7 month improvement in median RFS and a 16.6 month improvement in median OS compared with BDX-001 positive subject samples treated with placebo and gemcitabine. There was no difference in RFS or OS in the gemcitabine-alone arm based on BDX-001 selection.

Phase 2 – Non-Small Cell Lung Cancer (NSCLC)

GI-4000-03 was 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 . The objectives for the study were to evaluate immune response and safety. The study met its primary efficacy endpoint with 50% of the GI-4000 treated subjects showing Ras-specific T cell responses.

Survival results from the Stage I and III GI-4000 treated subjects were compared to 64 Stage I and III Ras mutation-positive NSCLC patients not enrolled in the trial but treated and followed at MSKCC over the same period of time as the GI-4000-03 study. We believe these 64 patients are useful as a comparison group because they were treated at the same institution over the same time period. We refer to these 64 patients as case-matched controls. We used a statistical adjustment to account for differences in baseline characteristics when comparing the results of the GI-4000 treated subjects to the case-matched control group using Kaplan Meier estimates of survival.

GI-4000 treated subjects demonstrated a trend for improved 1-, 2- and 3-year overall survival relative to the case-matched control group. At Year 1, all GI-4000-treated subjects were alive vs. 93% of control subjects. At Year 2, all GI-4000-treated subjects were alive vs. 88% of control subjects. At Year 3, 92% of GI-4000-treated subjects were alive vs. 83% of control subjects. These data were not statistically significant.