Phase I Study of Ad5-hGCC (Human Guanylyl Cyclase C)-PADRE in Stage I/II Colon Cancer
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||A Phase I Study of Guanylyl Cyclase C (GCC)-Encoding Replication-Deficient Human Type 5 Recombinant Adenovirus Vaccine (Ad5-hGCC-PADRE) in Stage I and II Colon Cancer Patients|
- Adverse events [ Time Frame: Continuous for 6 months after vaccination. ] [ Designated as safety issue: Yes ]Quantify treatment-emergent and related acute and sub-acute adverse events, serious adverse events, and Grade 3 and 4 non-laboratory abnormalities for safety assessments during the 6-month period after the injection of Ad5-hGCC-PADRE.
- Antibody responses [ Time Frame: One month following vaccination. ] [ Designated as safety issue: No ]Determine whether Ad5-hGCC-PADRE induces an antibody response to GCC at 1 month following vaccination with Ad5-hGCC-PADRE.
- T cell responses [ Time Frame: One month following vaccination. ] [ Designated as safety issue: No ]Determine whether Ad5-hGCC-PADRE induces a T cell response to GCC at 1 month following vaccination.
- Persistent immunological responses [ Time Frame: Three and six months after vaccination. ] [ Designated as safety issue: No ]Determine whether Ad5-hGCC-PADRE induces antibody and/or T cell responses to GCC that persist at 3 months and 6 months following vaccination.
- Occult metastases and immune responses [ Time Frame: One, thrree, and six months following vaccination. ] [ Designated as safety issue: No ]Determine whether antibody and/or T cell responses to GCC following vaccination with Ad5-hGCC-PADRE are related to occult metastases in regional lymph nodes quantified by GCC qRT-PCR.
- Race and immune responses [ Time Frame: One, three and six months following vaccination. ] [ Designated as safety issue: No ]Determine whether antibody and/or T cell responses to GCC following vaccination with Ad5-hGCC-PADRE are related to race.
- Time to recurrence and disease-free survival and immune responses [ Time Frame: Annually for 5 years from the time of vaccination ] [ Designated as safety issue: No ]Determine whether antibody and/or T cell responses to GCC following vaccination with Ad5-hGCC-PADRE are related to time to recurrence and/or disease-free survival during the 5-year period after the injection of Ad5-hGCC-PADRE.
|Study Start Date:||October 2013|
|Estimated Study Completion Date:||December 2018|
|Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Experimental: Ad5-hGCC-PADRE Vaccine
Biological: Ad5-hGCC-PADRE vaccine
A single intramuscular dose (100 billion virus particles) of Ad5-hGCC-PADRE vaccine.
There is an unmet need for improved therapeutic paradigms in colorectal cancer, the 3rd leading cause of cancer and 2nd leading cause of cancer mortality worldwide. This need is underscored by the populations in jeopardy, including the ~100 million people in the US over 50 y that have a 1:8 risk associated with a disease-specific mortality of 50%. Mortality reflects metastatic disease: ~50% of patients initially present with regional or distant metastases, while ~20% present with occult metastases. Beyond the general population risk, there is an established stage-specific difference in outcomes in pN0 (node negative) African Americans with colorectal cancer, who exhibit ~40% excess mortality attributable to race. Reductions in mortality have been hampered by the absence of effective chemo-, radio-, and immuno- therapeutic approaches to metastatic disease. In that context, immunotherapy has been disappointing, in part, reflecting the absence of antigens that are tumor-specific, immunogenic, and universally associated with neoplasia. Moreover, the gap in survival between African Americans and Caucasians specifically reflects the inability to identify those with occult metastases who are at increased risk for developing recurrent disease.
This study advances an emerging paradigm in colorectal cancer cell detection and eradication, employing GCC as a molecular marker and immunological target. GCC is a protein whose expression is normally restricted to intestinal epithelial cells, but universally expressed by metastatic colorectal tumors. We have clinically validated the detection of occult metastases in lymph nodes by quantifying GCC mRNA (messenger RNA) by reverse transcriptase (RT)-PCR (qRT-PCR). This study revealed that occult metastases were the most powerful independent predictors of survival in pN0 patients. Further, there is a disproportionate burden of occult disease in African American, compared to Caucasian, patients. This new molecular staging platform provides a unique opportunity to identify occult metastases underlying racial disparities in disease recurrence, which could be prevented by tumor-targeted immunotherapy.
In the absence of ideal tumor antigens, immunotherapy has been directed to tissue-specific proteins. Barriers to employing self-antigens include tolerance, which limits anti-tumor immunity, and autoimmunity. The present study advances an emerging paradigm exploiting immunological compartmentalization of mucosally-restricted antigens to generate systemic antitumor immunity without autoimmunity. Asymmetry in immunological cross-talk between compartments, wherein systemic T and B cell responses rarely extend to mucosae, suggest that proteins normally expressed in mucosae, but which are expressed systemically by tumors, may serve as vaccine targets for metastases. Advantages of these cancer mucosa antigens include unique systemic immunoreactivity profiles supporting highly effective durable antitumor immunity in the context of absent immunological cross-talk between compartments restricting autoimmunity. Here, this paradigm will be advanced employing the tumor marker GCC, which induces immune responses that oppose metastatic colorectal cancer in preclinical models, without autoimmunity. This study will define the safety and immunological efficacy of adenoviral GCC vaccine in African American and Caucasian pN0 colon cancer patients with excess recurrence risk reflecting occult lymph node metastases identified by GCC qRT-PCR. This study will be the first step in translating GCC into a vaccine for the secondary prevention of metastases in African American and Caucasian colorectal cancer patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01972737
|United States, Pennsylvania|
|Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|Study Director:||Scott A Waldman, MD, PhD||Thomas Jefferson University|