| Eligibility |
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) 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
- Absolute neutrophil count >= 1,500/microliter
- Estimated glomerular filtration rate (eGFR) (or creatinine clearance calculated using
the Cockcroft-Gault equation) = 60 mL/min/1.73m^2 (mL/min, within institutional 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 enrolled
with higher total bilirubin if their direct bilirubin is =< 1.5 times the ULN
- Participants must consent to refrain to receive any other type of vaccination during
the first 10 weeks of the trial
- Participants must consent to refrain from receiving adenoviral-based vaccines for the
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 the final
approved protocol
- The effects of Nous-209 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 for the duration of study participation (12 months)
and 6 months after end of study. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her study physician
immediately
- Ability to understand and the willingness to sign a written informed consent document
(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 criteria
for participation in study Cohort 1
- Participants must have completed all baseline procedures and received a complete cycle
of GAd20- 209 FSP (prime) and MVA-209-FSP (boost) vaccination per protocol for Cohort
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 endpoint as
specified for Cohort 1. Only participants with evaluable and proved immunogenicity
response at Week 9 are eligible for participation in Cohort 2
- Participants must consent to refrain from receiving any other type of vaccination
during weeks 52 to 68 of the trial
- Participants must consent to refrain from receiving adenoviral-based vaccines for the
duration of the trial (including the period from week 52 to week 68)
- Participants must consent to refrain from using aspirin or non-steroidal
anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX) inhibitors for the duration
of the cohort 2, except for cardiopreventive 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
- Female participant must agree to a pregnancy test at week 52
Exclusion Criteria:
- Prior receipt of a recombinant adenoviral or MVA vaccine including COVID19 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
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