Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients

NCT05078866 | Active Not Recruiting Phase 1 DMC FDA Drug

• 5 other identifiers: NCI-2021-107992022-0065MDA21-06-01P30CA016672UG1CA242609
• Study Type: interventional
• Target: 45
• Locations: 2 countries
• Sites: 4

Brief Summary

This phase Ib/II trial evaluates the safety and effect of the Nous-209 vaccine in Lynch syndrome patients. Lynch syndrome is an inherited disorder in which affected individuals have a higher-than-normal chance of developing colorectal cancer and certain other types of cancer, often before the age of 50. In Lynch syndrome, errors in the genetic information inside cells are not properly corrected. When that happens, the cells produce new proteins called neoantigens. Neoantigens are recognized by the body's immune system as foreign, and the body tries to get rid of them. Nous-209 is a vaccine made with man-made copies of some of those neoantigens. This trial aims to see whether the Nous-209 vaccine is safe to give to patients with Lynch syndrome, whether people are able to take the Nous-209 vaccine without becoming too uncomfortable, and how the immune system of patients with Lynch syndrome respond to the Nous-209 vaccine. This trial may help researchers determine whether receiving Nous-209 have an effect on the development of polyps or tumors in the colon.

Conditions

Colorectal Carcinoma; Lynch Syndrome

Outcome Measures

Primary Outcomes (4)

• Rates of grade 2/3 adverse events and symptom reactivity following vaccination

  Up to 12 months

• Rate of immunogenicity following vaccination (Cohort I)

  Immunogenicity will be defined as reactivity to at least 1 of 16 synthetic FSP pools using an enzyme-linked immune absorbent spot (ELISpot) assay. The rate of immunogenicity induced by Nous-209 will be reported along with its 95% exact (Clopper-Pearson) confidence interval.

  Baseline and week 9

• Rate of immunogenicity following revaccination (Cohort II)

  Immunogenicity will be defined as reactivity to at least 1 of 16 synthetic FSP pools using an enzyme-linked immune absorbent spot (ELISpot) assay. The rate of immunogenicity induced by Nous-209 will be reported along with its 95% exact (Clopper-Pearson) confidence interval.

  Weeks 52 and at 8 weeks after the last boost with MVA-209-FSP (corresponding to week 68 and week 60, for arm A and B, respectively)

• Rates of grade 2/3 adverse events and symptom reactivity following revaccination (Cohort II)

  Up to 12 months

Secondary Outcomes (9)

• Changes in T cell immune profile and T cell receptor (TCR) repertoire in the peripheral blood

  Baseline up to 12 months

• Changes in TCR repertoire within histologically normal colorectal mucosal

  Baseline to 12 months

• Changes in the gene expression profile and TCR repertoire of tumor infiltrating lymphocytes (TIL) within colorectal adenomas

  Baseline to 12 months

• T cell cytotoxicity against matched colorectal adenoma organoids

  At 12 months

• Percentage change in the number of colorectal adenomas, advanced neoplasia, and/or carcinomas

  At 12 months

Study Arms (3)

Part I (GAd20-209-FSPs, MVA-209-FSPs)

EXPERIMENTAL

Patients receive GAd20-209-FSPs IM on day 1 and MVA-209-FSPs IM at week 8. Patients undergo endoscopy with biopsy during screening and follow up as well as blood sample collection on the trial.

Biological: Adenoviral Tumor-specific Neoantigen Priming Vaccine GAd-209-FSP; Procedure: Biospecimen Collection; Procedure: Endoscopic Biopsy; Biological: MVA Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP; Other: Questionnaire Administration

Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs)

EXPERIMENTAL

Patients receive GAd20-209-FSPs IM at week 52 and MVA-209-FSPs IM at week 60. Patients undergo endoscopy with biopsy as well as blood sample collection on the trial.

Biological: Adenoviral Tumor-specific Neoantigen Priming Vaccine GAd-209-FSP; Procedure: Biospecimen Collection; Procedure: Endoscopic Biopsy; Biological: MVA Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP; Other: Questionnaire Administration

Part II Arm B (MVA-209-FSPs)

EXPERIMENTAL

Patients receive MVA-209-FSPs IM at week 52. Patients undergo endoscopy with biopsy as well as blood sample collection on the trial.

Procedure: Biospecimen Collection; Procedure: Endoscopic Biopsy; Biological: MVA Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP; Other: Questionnaire Administration

Interventions

MVA Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP BIOLOGICAL

Given IM

Also known as: Modified Vaccinia Ankara Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP, Modified Vaccinia Virus Ankara Tumor-specific Neoantigen Boosting Vaccine MVA-209-FSP, MVA-209-FSP

Part I (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm B (MVA-209-FSPs)

Adenoviral Tumor-specific Neoantigen Priming Vaccine GAd-209-FSP BIOLOGICAL

Given IM

Also known as: GAd-209-FSP, GAd20-209-FSP, Great Ape Adenoviral Tumor-specific Neoantigen Priming Vaccine GAd-209-FSP

Part I (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Part I (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm B (MVA-209-FSPs)

Endoscopic Biopsy PROCEDURE

Undergo endoscopy with biopsy

Also known as: Endoscopy and Biopsy

Part I (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm B (MVA-209-FSPs)

Questionnaire Administration OTHER

Ancillary studies

Part I (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm A (GAd20-209-FSPs, MVA-209-FSPs); Part II Arm B (MVA-209-FSPs)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have a clinical diagnosis of Lynch syndrome (LS) as defined by:
• Mutation-positive LS: documented carriers (or obligate carriers by pedigree) of a germline mutation in MMR genes (MLH1, MSH2/EPCAM, MSH6, or PMS2) that is deleterious/pathogenic or suspected to be deleterious/pathogenic (known or predicted to be detrimental/loss of function, respectively). The mutation must have been identified through a Clinical Laboratory Improvement Act (CLIA)-approved laboratory setting or an equivalent international agency. Final determination of eligibility for any discordant results in pathogenicity of the mutation will be determined by the study investigator. A formal eligibility exception in those instances will not be required as long as approval by the overall study principal investigator (PI) has been granted and documented
• Mutation-negative LS (also known as "Lynch-like syndrome" or "suspected Lynch syndrome): individuals with both of the following:
• A personal history of a non-sporadic MMR-deficient premalignant lesion (i.e., colorectal polyp) or a non-sporadic MMR-deficient malignant tumor, where "non-sporadic MMR deficiency" is defined by (1) the loss of MLH1, MSH2, MSH6, or PMS2 expression by immunohistochemistry (IHC), or (2) the detection of MSI by PCR or both, but no evidence of MLH1 promoter methylation in cases with loss of both MLH1 and PMS2, All testing must have been performed in accordance with local institutional guidelines in a CLIA- approved setting. (Note: central confirmation of MMR expression status, MSI, MLH1 promoter methylation or BRAF mutation is not required.); and
• Documented results of germline mutation testing performed in a CLIA-approved laboratory environment, demonstrating either a variant of unknown significance in MMR genes or the lack of a clinically significant variant in MMR genes; or, documentation that the individual declined to undergo germline MMR genetic testing
• Participants must have no evidence of active or recurrent invasive cancer for 6 months prior to screening
• Participants must be at least 6 months from any prior cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy, hormonal therapy, or radiation)
• Participants must have endoscopically accessible distal colon and/or rectal mucosa (i.e., participants must have at least part of the descending/sigmoid colon and/or rectum intact)
• Participants must consent to standard of care surveillance with colonoscopy with biopsies every 12 months
• Participants must consent to refrain from using aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX) inhibitors for the duration of the trial, except for cardio-preventive aspirin (\< 100 mg daily). Individuals taking such drugs may not be enrolled unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 1 month prior to enrollment. Participants will discuss with their primary care provider/local provider about the discontinuation of such medication(s) and obtain approval prior to stopping any agent
• Age \>= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of Nous-209 in participants \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
• Hemoglobin \>= 10 g/dL or hematocrit \>= 30 %
• Leukocyte count \>= 3,500/microliter
• Platelet count \>= 100,000/microliter

You may not qualify if:

• Prior receipt of a recombinant adenoviral or MVA vaccine including COVID-19 adenovirus vaccines within the previous 6 months
• Histologically-confirmed high-grade dysplasia or cancer on biopsy at screening
• Individuals with active malignancy (excluding non-melanoma skin cancer)
• Any serious uncontrolled and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures
• Active infection (acute and self-limited) or human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Participants with laboratory evidence of cleared HBV and HCV infection will be permitted
• History of organ allograft or other history of immunodeficiency
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients, or to egg proteins
• Individuals with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications (such as infliximab, rituximab, adalimumab, tacrolimus) within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Pregnant or breastfeeding or planning to become pregnant within 6 months after the end of study. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with Nous-209, breastfeeding should be discontinued if the mother is treated with Nous-209
• Men attempting or planning to conceive children during the study or within 6 months after the end of the study
• Participants may not be receiving any other investigational agents
• Cohort 2 only: participants who experienced grade 3 or higher AEs attributed to study drug in Cohort 1, excluding reactogenicity events

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Puerto Rico

San Juan, 00936, Puerto Rico

Location

Related Publications (1)

• D'Alise AM, Willis J, Duzagac F, Hall MJ, Cruz-Correa M, Idos GE, Thirumurthi S, Ballester V, Leoni G, Garzia I, Antonucci L, De Marco L, Micarelli E, Deng N, Secli L, Gogov S, Dong W, Jack Lee J, Bowen CM, Vornik LA, Garcia-Gonzalez A, Reyes-Uribe L, Richmond E, Umar A, Brown PH, Sinha KM, Rodriguez LM, Scarselli E, Vilar E. Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial. Nat Med. 2026 Jan 16. doi: 10.1038/s41591-025-04182-9. Online ahead of print.

  PMID: 41545594 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis

Interventions

Specimen Handling; Endoscopic Mucosal Resection; Endoscopy; Biopsy

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytodiagnosis; Cytological Techniques

Study Officials

• Eduardo Vilar-Sanchez

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2021
• First Posted: October 15, 2021
• Study Start: November 10, 2022
• Primary Completion: April 16, 2025
• Study Completion (Estimated): September 30, 2026
• Last Updated: March 3, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

US (3); PR (1)