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GUCY2C Prime-Boost Vaccination for Advanced Colorectal and Small Bowel Adenocarcinomas

ConditionsColorectal CancerSmall Bowel Adenocarcinoma
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorThomas Jefferson University

About this trial

This is an open-label, non-randomized, single-center, dose-escalation Phase 1 trial using a heterologous prime-boost strategy of vaccination with Ad5.F35-hGUCY2C-PADRE and recombinant Listeria monocytogenes (Lm-GUCY2C) vaccines in patients with advanced solid tumors including colorectal cancer, and small bowel adenocarcarcinomas who have progressed on available standard therapies. The study treatment will begin with Ad5.F35-hGUCY2C-PADRE vaccine administered intramuscularly (IM) once at the recommended Phase 2 dose (RPTD) dose, followed four weeks later by two administrations of Lm-GUCY2C intravenously (IV) at one of three escalating dose levels, four weeks apart. Treatment-related toxicity and development of immune responses will be evaluated every four weeks through week 8 after initial Lm-GUCY2C vaccination. Primary endpoints will include maximum tolerated dose (MTD) and safety and tolerability as measured by treatment emergent adverse events (TEAEs) and clinically significant changes in safety laboratory tests in the dose limiting toxicity (DLT) evaluation period defined as 4 weeks after the initial Lm-GUCY2C vaccination.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Males or females aged ≥ 18 years

Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Histologically or cytologically diagnosed, locally advanced or metastatic adenocarcinomas of colorectum or small bowel that have progressed after standard of care therapy or for which no standard therapy exists. Patients for whom standard therapies are intolerable or considered clinically inappropriate by the Investigator are eligible. If a patient refused available standard therapy or Investigator determined standard therapy was inappropriate, the reason for refusal or Investigator determination should be documented.

Patients with MSS CRC or small bowel adenocarcinoma must have received at least 1) a fluoropyrimidine, 2) oxaliplatin or irinotecan, and 3) a VEGF/VEGF receptor inhibitor unless deemed clinically inappropriate, refused by the patient, or not considered standard practice per institutional standards.

Disqualifiers

History of splenectomy

History of infection with listeriosis or has prior serious reaction to adenovirus

Infection requiring systemic antibiotics within 1 week prior to administration of study intervention

Topical, ocular, intra-articular, intranasal, and inhalation corticosteroids (with minimal systemic absorption)

Trial design

Design model

Sequential

Treatments tested in this trial

  • Ad5.F35-hGUCY2C-PADRE vaccine

    Biological/Vaccine

    Ad5.F35-hGUCY2C-PADRE vaccine administered as a single intramuscular injection at a dose of 5 × 10¹² viral particles as the priming vaccination in a heterologous prime-boost vaccination regimen.

  • Lm-GUCY2C vaccine

    Biological/Vaccine

    Lm-GUCY2C vaccine administered as an intravenous infusion at dose levels 1 x 10⁸, 3 x 10⁸, 1 x 10⁹, and 3 x 10⁹ colony-forming units (CFU) as booster vaccinations given twice approximately four weeks apart following Ad5.F35-hGUCY2C-PADRE priming.

  • CT Scan

    Diagnostic test

    Spiral CT of thorax, abdomen, and pelvis (and other imaging studies as clinically indicated) for disease assessment at Screening and EOT. If a subject cannot have a CT scan (e.g., allergy to contrast dye), MRI results are acceptable.

Treatment groups

18 Participants
are divided into 4 treatment groups
Group A: Arm 1 Dose Level -1: Lm-GUCY2C 1 x 10⁸Experimental treatment 3 interventions
Group B: Arm 2 Dose Level 1: Lm-GUCY2C 3 x 10⁸Experimental treatment 3 interventions
Group C: Arm 3 Dose Level 2: Lm-GUCY2C 1 x 10⁹Experimental treatment 3 interventions
Group D: Arm 4 Dose Level 3: Lm-GUCY2C 3 x 10⁹Experimental treatment 3 interventions

Trial outcomes

Primary outcomes

1

Rate of Dose Limiting Toxicities (DLT) to determine recommended Phase 2 dose (RPTD) of Lm-GUCY2C vaccine boosts following Ad5.F35-hGUCY2C-PADRE vaccine

Number of Participants who experience a dose-limiting toxicity

Time frame
28 days after first Lm-GUCY2C vaccination
2

Number of patients with dose limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period

Number of participants who experience at least once dose-limiting toxicity during the maximum tolerated dose (MTD) evaluation period.

Time frame
28 days after first Lm-GUCY2C vaccination

Secondary outcomes

1

Number of Treatment Emergent Adverse Events (TEAEs) as defined by the Common Terminology Criteria for Adverse Events version 5 (CTCAE v5)

Number of participants experiencing treatment-emergent adverse events following administration of study vaccines.

Time frame
Up to 1 year after first vaccination
2

T-cell Responses to GUCY2C measured by enzyme-linked immunosorbent spot (ELISpot) assay

Antibody and T-cell data will be summarized by positive response rates (each subject recorded as yes/no) and exact 2-sided 95% confidence intervals. For this study, a small GUCY2C-specific T-cell response can be expected after Ad5.F35-hGUCY2C-PADRE, but a significant T-cell response is expected at Days 29 and 57 (four weeks after each Lm-GUCY2C dose). Significance of the change from baseline will be assessed using the modified distribution-free resampling (DFR) method. A subject with a response at either Day 29 or Day 57 will be considered a responder. Supporting analysis will model the trajectory of GUCY2C-specific T-cell responses over time using mixed effects linear regression.

Time frame
Baseline through Week 12 after first vaccination with optional collections and analyses until end of follow-up (when all subjects reach 24 months of follow-up)
3

Humoral Responsess to GUCY2C

(pan-Ig) ELISA will be used to detect responses, which will be graded on a scale of mean absorbance at 405 nm. Some GUCY2C-specific humoral response may be detectable at Day 29, but a stronger response is expected at measurement on Day 57. Subjects that fail to produce an end-point titer (no dilution is greater than pre-treatment) by Day 57 will be considered non-responders. Otherwise, responses will be measured on a continuous basis and compared both within and among cohorts at the end of the study. Supporting analysis will model the trajectory of GUCY2C-specific pan-Ig responses over time using mixed effects linear regression.

Time frame
Baseline through Week 12 after first vaccination with optional collections and analyses until end of follow-up (when all subjects reach 24 months of follow-up)
4

Change in ctDNA Levels

Baseline measurement of circulating tumor DNA (ctDNA) will occur prior to beginning therapy with any administration of a vaccine. This will be used as a baseline for comparison at other time points throughout the study (increasing or decreasing if positive or negative). ctDNA will be measured at Days 29 and 57, and measurements will be categorized into one of five possible results at each time points: 1) decrease from baseline, 2) increase from baseline, 3) conversion from positive to negative, 2) conversion from negative to positive, and 5) maintenance of negative result. The time of conversion will be notated, where applicable.

Time frame
Baseline through Week 12 after first vaccination with optional collections and analyses until end of follow-up (when all subjects reach 24 months of follow-up)

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Thomas Jefferson University

Lead sponsor

United States Department of Defense

Collaborator

Source ClinicalTrials.gov
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