Testing a Combination of Vaccines for Cancer Prevention in Lynch Syndrome
Study Details
Study Description
Brief Summary
This phase IIb trial tests whether Tri-Ad5 in combination with N-803 works to prevent colon and other cancer in patients with Lynch syndrome. Each of the three injections in Tri-Ad5 vaccine contain a different substance that is in precancer and cancer cells. Injecting these substances may cause the immune system to develop a defense against cancer that recognizes and destroys any precancer and cancer cells that produce these proteins in the future. N-803 may increase immune responses to other vaccines. Giving Tri-Ad5 in combination with immune enhancing N-803 may lower the change of developing colon and other cancer in patients with Lynch syndrome.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To evaluate if the combination of trivalent adenovirus-5 (Tri-Ad5) vaccines and IL-15 superagonist nogapendekin alfa inbakicept (N-803) reduces the incidence of colorectal neoplasms in patients with Lynch syndrome (LS).
SECONDARY OBJECTIVES:
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To evaluate the safety and tolerability of the Tri-Ad5 vaccines + N-803 in combination.
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To correlate clinical factors such as use of aspirin and non-steroidal anti-inflammatory drugs (NSAID), smoking and alcohol intake with immune responses.
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To evaluate the effect of Tri-Ad5 vaccines on the incidence of LS-related extracolonic cancers.
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To systematically measure the participants' behavior and experience in terms of vaccine uptake, cancer-specific distress and quality of life.
EXPLORATORY OBJECTIVES:
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To determine the ability of the Tri-Ad5 vaccines + N-803 to generate a 2-fold increase in T cell responses (cell-mediated immunity) at week 12 (early immune response) and at week 56 (long-term memory response).
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To evaluate circulating anti-MUC1 IgG (antibody-mediated immunity) after Tri-Ad5 vaccines
- N-803 III. To compare the expression of the three tumor associated antigen (TAAs): MUC1, carcinoembryonic antigen (CEA) and brachyury in colorectal neoplasms before and after Tri-Ad5 vaccines + N-803.
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To evaluate changes in the immune profile and abundance of resident immune cell types in colonic mucosa after vaccination with Tri-Ad5 vaccines + N-803 using messenger ribonucleic acid sequencing (mRNAseq) and immunohistochemistry (IHC).
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To test the effects of the vaccines alone or in combination with N-803 on specific immune subsets of peripheral blood mononuclear cells (PBMCs) and serum soluble factors and cytokines.
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To compare the expression of stem cell markers in colorectal neoplasms before and after Tri-Ad5 vaccines + N-803.
OUTLINE:
SAFETY PHASE I: Patients receive Tri-Ad5 subcutaneously (SC) at weeks 0, 4, 8, and 52. Patients also undergo standard of care (SOC) colonoscopy at baseline, at 52 weeks and 104 weeks.
SAFETY PHASE II: Patients receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline, 52 weeks and 104 weeks.
RANDOMIZED CONTROL PHASE: Patients are randomized into 1 of two arms.
ARM I: Patients receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 and 104 weeks.
ARM II: Patients receive placebo SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 and 104 weeks.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (Tri-Ad5, N-803) Patients receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 and 104 weeks. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Colonoscopy
Undergo SOC colonoscopy
Drug: Nogapendekin Alfa
Given nogapendekin alfa inbakicept (N-803) SC
Other Names:
Other: Questionnaire Administration
Ancillary studies
Biological: Vaccine Therapy
Given Tri-Ad5 vaccine SC
|
| Placebo Comparator: Arm II (placebo) Patients receive placebo SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 and 104 weeks. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Colonoscopy
Undergo SOC colonoscopy
Drug: Placebo Administration
Given SC
Other: Questionnaire Administration
Ancillary studies
|
| Experimental: Safety phase I (Tri-Ad5) Patients receive Tri-Ad5 subcutaneously (SC) at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 weeks and 104 weeks. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Colonoscopy
Undergo SOC colonoscopy
Other: Questionnaire Administration
Ancillary studies
Biological: Vaccine Therapy
Given Tri-Ad5 vaccine SC
|
| Experimental: Safety phase II (Tri-Ad5 , N-803) Patients receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Patients also undergo SOC colonoscopy at baseline and at 52 weeks and 104 weeks. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Colonoscopy
Undergo SOC colonoscopy
Drug: Nogapendekin Alfa
Given nogapendekin alfa inbakicept (N-803) SC
Other Names:
Other: Questionnaire Administration
Ancillary studies
Biological: Vaccine Therapy
Given Tri-Ad5 vaccine SC
|
Outcome Measures
Primary Outcome Measures
- Cumulative incidence rate of the composite endpoint of adenomas (tubular, tubulovillous and serrated), advanced adenomas and colon cancer [At 104 weeks]
Will be compared between the two arms using a stratified Mantel-Haenszel test where the randomization stratification factors will be included as strata. The cumulative events rates will be reported for each study arm along with the corresponding two-sided 95% confidence intervals.
Secondary Outcome Measures
- Association of clinical factors with immune responses [At 104 weeks]
Will be evaluated by conducting univariate and multivariate binary regression analyses. These analyses will be conducted for both arms combined (in which case arm is included as a stratification factor in the model) and each arm separately. The proportions of cells within adenomas expressing stem cells markers pre- and post-vaccination will be compared within each study arm using the signed rank test, and within-subject changes will be compared between responders and non-responders using Wilcoxon rank-sum test for each arm separately and both arms combined. Comparisons between study arms will be conducted using a Wilcoxon rank-sum test.
- Incidence of extracolonic neoplasms [At 104 weeks]
Will compare the observed incidences of lynch syndrome (LS)-related extracolonic cancers to historical control incidence of LS-related extracolonic cancers in this patient population. We will collect the information about extracolonic cancers by asking the participants and by reviewing the pathology reports for confirmation.
Other Outcome Measures
- Number of antigen-specific T-cells, peripheral blood mononuclear cells (PBMCs), serum soluble factors and antibody levels [At baseline, 12 weeks, and 56 weeks]
Will be log-transformed before conducting any analyses. Comparisons of number of antigen-specific T-cells, PBMCs, serum soluble factors and antibodies between study arms will be conducted using a nonparametric Wilcoxon rank sum test. IgG titers that will be measured serially will be analyzed and compared between the two arms using linear mixed effects models. If zero-inflation is detected, generalized linear mixed models with zero-inflated Poisson or negative binomial distributions will be fitted.
- Prevalence of immune cells markers, tumor associated antigens (TAAs) and stem cell markers [Baseline, 52 weeks, and 104 weeks]
Will be reported using repeated measures techniques. We will also compare pre- and post-vaccination size, number and histology of polyps.
- Differential expression analyses [At baseline, 52 weeks, and 104 weeks]
Will be using Bioconductor R package DESeq2. A paired sample design to compare post- to pre-vaccination samples within each study arm and for both arms combined. Significant genes with Benjamini-Hochberg (BH)-adjusted p-value =< 0.05 and absolute value of log2-fold change >= 0.5 will be annotated with pathways of interest in volcano plots.
- Immune cell gene enrichment analysis [At baseline, 52 weeks, and 104 weeks]
Will be calculated using raw read counts with Bioconductor R package GSVA.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participants with LS defined as one of the following:
-
Mutation positive: MLH1, MSH2/EPCAM and MSH6 genotypes with prior history of >= 1 adenoma(s) and/or >= 1 advanced adenoma(s) and/or colon cancer(s) (but no active cancer for 6 months) OR
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PMS2 genotype with prior history of colon cancer(s) (but no active cancer for 6 months)
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Participants must have at least part of the descending/sigmoid colon and/or rectum intact
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Participants must be at least 6 months from any cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy or radiation)
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Participants older than 18 years will be enrolled. Because the risk of LS related cancers is very low in participants < 18 years of age, children are excluded from this study
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Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky 70%)
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Leukocytes >= 3,000/microliter
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Absolute neutrophil count >= 1,500/microliter
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Platelets >= 100,000/microliter
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Total bilirubin within normal institutional limits
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal
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Creatinine within normal institutional limits
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The effects of the Tri-Ad5 vaccines and N-803 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
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Ability to understand and the willingness to sign a written informed consent document
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Participants must be willing and able to space COVID vaccines at least 2 weeks prior to and 2 weeks after receipt of study agent
Exclusion Criteria:
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History of organ allograft or other history of immunodeficiency
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Known human immunodeficiency virus (HIV) with CD4 count < 540, Hepatitis B virus (HBV), or Hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted. Poorly controlled HIV may prevent an adequate immune response to the vaccine and will be an exclusion criterion
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Subjects requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 3 months of vaccination
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Participants may not be receiving any other investigational agents
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History of allergic reactions attributed to compounds of similar chemical or biologic composition to adenovirus-based vaccines and N-803
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active autoimmune diseases, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
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Pregnant women are excluded from this study because of the unknown effects of the vaccine and N-803 on the fetus. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with the vaccine plus N-803, breastfeeding should be discontinued if the mother is treated with the vaccine plus N-803
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History of untreated thrombotic disorders
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Participants who experienced severe side effects or allergic reactions to previous adenovirus-based vaccines (such as Johnson and Johnson COVID vaccine) will be excluded
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic Hospital in Arizona | Phoenix | Arizona | United States | 85054 |
| 2 | University of Arizona Cancer Center - Prevention Research Clinic | Tucson | Arizona | United States | 85719 |
| 3 | University of Colorado | Denver | Colorado | United States | 80217-3364 |
| 4 | Northwestern University | Chicago | Illinois | United States | 60611 |
| 5 | University of Kansas Cancer Center | Kansas City | Kansas | United States | 66160 |
| 6 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 7 | University of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan | United States | 48109 |
| 8 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
| 9 | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
| 10 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 11 | Ohio State University Comprehensive Cancer Center | Columbus | Ohio | United States | 43210 |
| 12 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 13 | Huntsman Cancer Institute/University of Utah | Salt Lake City | Utah | United States | 84112 |
| 14 | University of Puerto Rico | San Juan | Puerto Rico | 00936 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Ajay Bansal, Northwestern University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2021-14234
- NCI-2021-14234
- NCI 21-05-01
- NWU21-05-01
- INT21-05-01
- P30CA060553
- UG1CA242596
- UG1CA242609
- UG1CA242632
- UG1CA242635
- UG1CA242643