A Vaccine (Ad5.F35-hGCC-PADRE) for the Treatment of Gastrointestinal Adenocarcinoma

This is an open-label, dose-finding, single-center, study of Ad5.F35-hGCC-PADRE vaccine delivered intramuscularly in subjects with colorectal, pancreatic, gastric, esophageal, or small bowel cancers who are at high risk of relapse without evidence of disease post definitive surgery and standard therapy. Study treatment will start after surgery and standard therapy. Subjects who meet the eligibility criteria can participate in this study at least four and no more than 24 weeks ± one week post-completion of standard treatment, after they have recovered from the side effects from previous therapies. Eligible subjects will be sequentially randomized into three treatment arms of 10¹¹, 10¹², and 5 × 10¹² virus particles Ad5.F35-hGCC-PADRE administered by IM injection once every four weeks (± one week) for a total of three administrations. An initial safety lead-in group of 9 subjects (3 in each group) will be randomized sequentially and further enrollment will be paused until they have completed 4 weeks of follow-up to ensure no dose-limiting toxicities (DLT). Moreover, the enrollment of the first 3 subjects will be staggered by an interval of 3 weeks to monitor for acute and subacute toxicities. Following the completion of assessment of the initial safety lead-in group, a meeting will be held with the PI and the TJU Medical Monitor to review the safety information. If no excessive rates of DLT are observed, enrollment will continue in each dosing arm with continuous monitoring of adverse events. A total of 27 subjects are planned to be randomized to each treatment arm. If it is determined safe to continue enrollment in each dosing arm, a formal letter from the Medical Monitor will be issued. After 15 patients in each cohort have completed treatment, a futility analysis will be conducted, and information will be informally reviewed with the Medical Monitor. In the expansion cohort, subjects with colon cancer who meet eligibility criteria will be enrolled after completing surgery and standard of care adjuvant chemotherapy. There is no limit to the amount of time since completing adjuvant therapies to enroll on this cohort. Subjects who are ctDNA+ by CLIA-certified standard of care assay and fulfil other eligibility criteria can enroll at any point post adjuvant therapies. Subjects will receive single IM vaccination with Ad5.F35-hGCC-PADRE at 5 × 10¹² vp. This dose is selected based upon preliminary efficacy data from first part of this study. Patients will be monitored for adverse events over the course of four weeks. Labs will be collected for immunomonitoring and ctDNA will be collected immediately prior to vaccination, at 4 weeks, 12 weeks and up to 52 weeks post-vaccination. Standard of care ctDNA assessments performed post-vaccination will be collected. Optional research blood samples will be collected for patients who opt in and will be collected every 3 months for up to 24 months or until disease recurrence or death whichever comes first. PRIMARY OBJECTIVES: 1. Evaluate the safety and tolerability of sequential Ad5.F35-hGCC-PADRE vaccine administration, delivered intramuscularly (IM) at three dose levels (10¹¹, 10¹², and 5 × 10¹² virus particles) four weeks apart in subjects with high-risk colorectal, pancreatic, gastric, esophageal, or small bowel adenocarcinomas with no evidence of disease after surgery and standard therapy. 2. For Cohort 2B, evaluate the safety and tolerability of single Ad5.F35-hGCC-PADRE vaccine at 5 × 10¹² vp dose level in MRD+ colon cancer patients with no evidence of radiographic disease 3. Evaluate the cellular (T-cell) responses to Ad5.F35-hGCCPADRE at three different dose levels (10¹¹, 10¹², and 5 × 10¹² virus particles) administered intramuscularly (IM) as three sequential doses four weeks apart in subjects with high-risk colorectal, pancreatic, gastric, esophageal, or small bowel adenocarcinomas with no evidence of disease after surgery and standard therapy. 4. For cohort 2B, evaluate the cellular (T-cell) responses to Ad5.F35-hGCC-PADRE vaccine at 5 × 10¹² vp dose administered IM as one dose in subjects with MRD+ colon cancer with no evidence of radiographic disease after surgery and standard therapy. EXPLORATORY OBJECTIVES: * Evaluate the humoral (antibody) responses to Ad5.F35-hGCC-PADRE at three different dose levels (10¹¹, 10¹², and 5 × 10¹² virus particles) administered IM as three sequential doses four weeks apart in subjects with high-risk colorectal, pancreatic, gastric, esophageal, or small bowel adenocarcinomas with no evidence of disease after surgery and standard therapy * Evaluate the association of neutralizing antibodies to Ad5 with immunologic response * Evaluate the correlation of the immune response to the GCC protein expression in tumors to assess immune tolerance * Evaluate disease-free survival (DFS) * Evaluate overall survival (OS), where feasible * Evaluate the circulatory tumor DNA (ctDNA) status and correlation with clinical recurrence, where feasible * Evaluate the ctDNA dynamics after single dose of 5 × 10¹² vp Ad5.F35-hGCC-PADRE vaccine in an expansion cohort of ctDNA+ colon cancer patients