Nous-209 Genetic Vaccine for the Treatment of Microsatellite Unstable Solid Tumors

Inclusion Criteria for Cohort C (Phase II)

In order to be eligible, the subject must:

Have the ability to comprehend and willingness to provide written informed consent (ICF) for the study.

Have previously proven microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status (confirmatory testing is not required);

• dMMR/MSI Testing: Subjects are eligible to the combined treatment based on previous diagnosis for dMMR/MSI status. dMMR/MSI status diagnosis should be performed locally in the past 6 months prior to study day 1, by IHC or NGS or PCR based tests that are certified per local requirements.

Subjects with locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) CRC who are eligible for anti-PD-1 1st line of treatment.
Be ≥18 years of age on day of signing informed consent.
Have a life expectancy of at least 6 months.
Have a performance status of 0 - 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 2 or less (except alopecia). If subject received major surgery or radiation therapy they must have recovered from the toxicity and/or complications from the intervention.
Have adequate hematological and blood chemistry values for Phase II as indicated in Table 2: Eligibility Criteria: hematological and blood chemistry values.
Not be previously treated with a (licensed or experimental) anti-PD-1 or anti-immunotherapy-drugs-are-boosting-survival/" >PD-L1 checkpoint inhibitor.
For up to 15 subjects in Cohort C and up to 10 subjects in Cohort D with the new vaccination scheme (i.e. GAd prime at week 1, MVA boosts at weeks 2, 4 and 7) only at selected sites: Agree to have a biopsy at baseline from a lesion that can be biopsied with an acceptable clinical risk (as judged by the Investigator in discussion with the interventional radiologist or endoscopist). An older (not older than 6 months) FFPE specimen from locations not radiated prior to biopsy can be accepted.
Have measurable disease per RECIST version 1.1.
Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Females: not be pregnant [see Appendix 6], not breastfeed, and must have at least one of the following conditions that apply:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR
A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 6 during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.
Male subjects: agree to use a contraceptive as detailed in Appendix 6 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Inclusion Criteria for Cohort D (Phase II):

In order to be eligible, the subject must:

Have the ability to comprehend and willingness to provide written informed consent (ICF) for the study.

Have previously proven microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status (confirmatory testing is not required);

• dMMR/MSI Testing: Subjects are eligible to the combined treatment based on previous diagnosis for dMMR/MSI status. dMMR/MSI status diagnosis should be performed locally in the past 6 months prior to study day 1, by IHC or NGS or PCR based tests that are certified per local requirements.

Subjects with locally advanced unresectable or metastatic MSI-H/ dMMR CRC who have had radiographic progression (PD) after having a best response of stable disease (SD) or better on/after anti-PD1 treatment.
May have progressed on additional approved therapy.
Be ≥18 years of age on day of signing informed consent.
Have a life expectancy of at least 6 months.
Have a performance status of 0 - 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 2 or less (except alopecia). If subject received major surgery or radiation therapy they must have recovered from the toxicity and/or complications from the intervention.

Have adequate hematological and blood chemistry values for Phase II as indicated in Table 2: Eligibility Criteria: hematological and blood chemistry values.

Table 2: Eligibility Criteria: hematological and blood chemistry values:

Absolute neutrophil count (ANC) >1500 / mm3 Platelets >70,000 / mm3 Hemoglobin >8 g/dL AST or ALT ≤5 x ULN Subject with liver metastases ≤5 x ULN Subject without liver metastases ≤2.5 x ULN ULN: Upper limit of normal; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase

For up to 15 subjects subjects in Cohort C and up to 10 subjects in Cohort D with the new vaccination scheme (i.e. GAd prime at week 1, MVA boosts at weeks 2, 4 and 7) only at selected sites: Agree to have a biopsy at baseline from a lesion that can be biopsied with an acceptable clinical risk (as judged by the Investigator in discussion with the interventional radiologist or endoscopist). An older (not older than 6 months) FFPE specimen from locations not radiated prior to biopsy can be accepted.
Have measurable disease per RECIST version 1.1.
Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Females: not be pregnant [see Appendix 6], not breastfeed, and must have at least one of the following conditions that apply:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR
A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 6 during the treatment period and for at least 180 days after the last dose of study treatment and refrain from egg donation during this period.
Male subjects: agree to use a contraceptive as detailed in Appendix 6 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Exclusion Criteria for Cohort C and D (Phase II)

The subject must be excluded from participating in if he/she:

Has a diagnosis of immunodeficiency, or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (have no evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any worsening of neurologic symptoms with respect to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to pembrolizumab.
Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs. Cohort C only: Had prior adjuvant treatment with an anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immunoregulatory receptors or mechanisms.
Cohort D only: discontinued prior therapy with a checkpoint inhibitor due to treatment-related toxicities.
Had prior allogeinic tissue or solid organ transplant.
Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.

Has known history of HIV (HIV1/2 antibodies). HIV-infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:

Participants on ART must have a CD4+ T-cell count 350 cells/mm3 at time of screening
Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening
Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1)
HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.

Had prior radiotherapy within 2 weeks of enrollment, or within 4 weeks of enrollment in the case of radiation to central nervous system (CNS), which requires

≥4-week washout. Subjects must have recovered from all radiation-related toxicities,not require corticosteroids, and not have had radiation pneumonitis. Some cases of local radiotherapy may be allowed with the Medical Monitor's approval. Note: A one-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease.

Has immunosuppression implying the continued use of systemic (at prednisone dose equivalent of >10 mg) or topical steroids at, or near, the planned intramuscular injection site or the use of immunosuppressive agents for any concurrent condition in the 4 weeks prior to first study treatment administration. Inhaled and eye drop-containing corticosteroids are permitted.

Has received a live-virus vaccination within 30 days of pembrolizumab start. Seasonal flu vaccines that do not contain live virus are permitted. Covid-19 vaccines are permitted under the following guidance: mRNA Covid-19 vaccines are permitted if administered more than 2 weeks prior to Study Day 1, and Covid19 Adenovirus-based vaccines are accepted if administrated at least 6 months before Study Day 1.

For any other Covid-19 vaccines or symptomatic treatment, please contact the study Medical Monitor. Administration of killed vaccines are allowed.

Has an active severe infection requiring therapy.
Has active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (i.e., positive hepatitis B surface antigen [HBsAg]). Subjects with negative HBsAg and positive total hepatitis B core antibody may be included if HBV DNA is undetectable at the time of screening. Subjects who are positive for HCV antibody are eligible only if the PCR test is negative for HCV RNA. Subjects with known current or prior HBV infection must have HBsAg and HBV DNA testing during screening and those with current or previous HCV infection must have HCV DNA testing.
Has a chronic illness including, but not limited to, chronic heart failure, coronary heart disease, cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements.
Has any history of anaphylaxis in reaction to a vaccination.
Is a woman who is pregnant or breastfeeding.
Any condition in the judgment of the Investigator, which makes the subject unsuitable for study participation; including psychological conditions.