Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients

Inclusion Criteria:

• INCLUSION CRITERIA FOR PARTICIPANTS IN COHORT 1:

• Participants must have a clinical diagnosis of Lynch syndrome (LS) as defined by:

• Mutation-positive LS: documented carriers (or obligate carriers by pedigree) ofa germline mutation in MMR genes (MLH1, MSH2/EPCAM, MSH6, or PMS2) that isdeleterious/pathogenic or suspected to be deleterious/pathogenic (known orpredicted to be detrimental/loss of function, respectively). The mutation musthave been identified through a Clinical Laboratory Improvement Act (CLIA)-approved laboratory setting or an equivalent international agency. Finaldetermination of eligibility for any discordant results in pathogenicity of themutation will be determined by the study investigator. A formal eligibilityexception in those instances will not be required as long as approval by theoverall study principal investigator (PI) has been granted and documented

• Mutation-negative LS (also known as "Lynch-like syndrome" or "suspected Lynchsyndrome): 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) thedetection of MSI by PCR or both, but no evidence of MLH1 promotermethylation in cases with loss of both MLH1 and PMS2, All testing musthave been performed in accordance with local institutional guidelines in aCLIA- approved setting. (Note: central confirmation of MMR expressionstatus, MSI, MLH1 promoter methylation or BRAF mutation is not required.);and

• Documented results of germline mutation testing performed in aCLIA-approved laboratory environment, demonstrating either a variant ofunknown significance in MMR genes or the lack of a clinically significantvariant in MMR genes; or, documentation that the individual declined toundergo germline MMR genetic testing

• Participants must have no evidence of active or recurrent invasive cancer for 6months prior to screening

• Participants must be at least 6 months from any prior cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy, hormonal therapy, orradiation)

• 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/orrectum intact)

• Participants must consent to standard of care surveillance with colonoscopy withbiopsies every 12 months

• Participants must consent to refrain from using aspirin or non-steroidalanti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX) inhibitors for the durationof the trial, except for cardio-preventive aspirin (< 100 mg daily). Individualstaking such drugs may not be enrolled unless they are willing to stop themedications (and possibly change to alternative non-excluded medications to treatthe same conditions) no less than 1 month prior to enrollment. Participants willdiscuss with their primary care provider/local provider about the discontinuation ofsuch medication(s) and obtain approval prior to stopping any agent

• Age >= 18 years. Because no dosing or adverse event (AE) data are currentlyavailable on the use of Nous-209 in participants < 18 years of age, children areexcluded from this study but will be eligible for future pediatric trials, ifapplicable

• 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

• Absolute neutrophil count >= 1,500/microliter

• Estimated glomerular filtration rate (eGFR) (or creatinine clearance calculatedusing the Cockcroft-Gault equation) ≥ 60 mL/min/1.73m^2 (mL/min, withininstitutional limits of normal)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 times the institutional upper limit of normal (ULN)

• Total bilirubin =< 1.5 the ULN; participants with Gilbert's disease may be enrolledwith higher total bilirubin if their direct bilirubin is =< 1.5 times the ULN

• Participants must consent to refrain from receiving any other type of vaccinationduring the first 10 weeks of the trial

• Participants must consent to refrain from receiving adenoviral-based vaccines forthe duration of the trial (including the period from week 9 to week 52)

• Willing and able to adhere to the prohibitions and restrictions specified in thefinal approved protocol

• The effects of Nous-209 on the developing human fetus at the recommended therapeuticdose are unknown. For this reason, women of child-bearing potential and men mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry for the duration of study participation (12 months)and 6 months after end of study. Should a woman become pregnant or suspect she ispregnant while participating in this study, she should inform her study physicianimmediately

• Ability to understand and the willingness to sign a written informed consentdocument (available for both English- and Spanish-speaking individuals)

• INCLUSION CRITERIA FOR PARTICIPANTS IN COHORT 2:

• Participants must have been confirmed eligible and met all study inclusion criteriafor participation in study Cohort 1

• Participants must have completed all baseline procedures and received a completecycle of GAd20- 209 FSP (prime) and MVA-209-FSP (boost) vaccination per protocol forCohort 1

• Participants must have undergone collection of research blood samples at baseline (week 0) and week 9 for evaluation of the Nous-209-induced immunogenicity endpointas specified for Cohort 1. Only participants with evaluable and provedimmunogenicity response at Week 9 are eligible for participation in Cohort 2

• Participants must consent to refrain from receiving any other type of vaccinationduring weeks 52 to 68 of the trial

• Participants must consent to refrain from receiving adenoviral-based vaccines forthe duration of the trial (including the period from week 52 to week 68)

• Participants must consent to refrain from using aspirin or non-steroidalanti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX) inhibitors for the durationof the cohort 2, except for cardiopreventive aspirin (< 100 mg daily). Individualstaking such drugs may not be enrolled unless they are willing to stop themedications (and possibly change to alternative non-excluded medications to treatthe same conditions) no less than 1 month prior to enrollment. Participants willdiscuss with their primary care provider/local provider about the discontinuation ofsuch medication(s) and obtain approval prior to stopping any agent

• Female participant must agree to a pregnancy test at week 52

Exclusion Criteria:

• Prior receipt of a recombinant adenoviral or MVA vaccine including COVID-19adenovirus 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 frommalignancy exception above), psychiatric disorder, or other conditions that couldinterfere with participant's safety, obtaining informed consent, or compliance tothe study procedures

• Active infection (acute and self-limited) or human immunodeficiency virus (HIV),hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Participants withlaboratory 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 drugschemically related to study drug, or excipients, or to egg proteins

• Individuals with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressivemedications (such as infliximab, rituximab, adalimumab, tacrolimus) within 14 daysof study drug administration. Inhaled or topical steroids and adrenal replacementdoses > 10 mg daily prednisone equivalents are permitted in the absence of activeautoimmune disease

• Pregnant or breastfeeding or planning to become pregnant within 6 months after theend of study. Because there is an unknown but potential risk for AEs in nursinginfants secondary to treatment of the mother with Nous-209, breastfeeding should bediscontinued if the mother is treated with Nous-209

• Men attempting or planning to conceive children during the study or within 6 monthsafter 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 tostudy drug in Cohort 1, excluding reactogenicity events