Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria for Cohorts A and B (Phase I):

In order to be eligible for participation in the Phase I of this trial (Cohorts A and B) the subject must:

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 in Cohorts A and B based on previous diagnosis for MSI status. MSI status diagnosis should have been performed locally by CLIA certified immunohistochemistry (IHC) or NGS or PCR based tests.

A. Subjects with unresectable or metastatic, microsatellite instability high (MSI-H) or mismatch repair deficient CRC, gastric or G-E junction tumors who have progressed following prior treatment (2nd or further line of treatment) or B. Subjects with unresectable or metastatic, microsatellite instability high (MSI-H) or mismatch repair deficient CRC, gastric or G-E junction tumors who must have refused, or have been considered ineligible for chemotherapy; or for whom a clinical trial of an investigational agent plus pembrolizumab is considered appropriate by the Investigator (1st line of treatment).

3. Be ≥18 years of age on day of signing informed consent. 4. Have a life expectancy of at least 6 months. 5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.

6. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 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.

7. Have adequate hematological and blood chemistry values as indicated in Table 1.

Table 1: Adequate Hematological and Chemistry Lab Values for Phase I Absolute neutrophil count (ANC) >1000 / mm3 Platelets >100,000 / mm3 Hemoglobin >9 g/dL or >5.6 mmol/L - 2 weeks without transfusions AST or ALT ≤2.5 x ULN Subject with liver metastases ≤5 ULN Alkaline phosphatase ≤5 x ULN Creatinine Clearance (Calculated by Cockcroft Gault glomerular filtration rate estimation) ≥50 mL/min 8. Not previously treated with a (licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.

9. Must agree to have a first 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) formalin-fixed paraffin-embedded (FFPE) specimen from locations not radiated prior to biopsy can be accepted.

10. Must agree to have a second on-treatment biopsy that will be taken only if not representing an unacceptable clinical risk and/or if technically feasible as judged by the Investigator in discussion with the interventional radiologist or endoscopist.

11. Participants with measurable disease per RECIST version 1.1. 12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive, or cannot be confirmed as negative, a serum pregnancy test will be required.

13. Females of reproductive potential must agree to use effective contraception for the entire study duration up to 4 months after the last dose of pembrolizumab and 60 days after the last dose of vaccine (see paragraph 6.10).

14. Male subjects of childbearing potential must agree to use effective contraception starting with the first dose of vaccine through 60 days after the last dose of vaccine (see paragraph 6.10).

15. Ability to understand and willingness to sign a written Informed Consent form.

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-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 Cohorts A and B (Phase I):

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

Has history of active or suspected autoimmune disease, including ulcerative colitis and Crohn's Disease, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g. Wegener's Granulomatosis]) or CNS or motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis) or autoimmune thyroiditis. Subjects with minor well controlled hypothyroidism may be enrolled. Autoimmune diagnoses not listed here must be approved by the medical monitor of the study.
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 respect to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 1 week prior to pembrolizumab.
Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs.
Is receiving growth factors including, but not limited to, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 4 weeks of study drugs administration.
Had prior treatment with an anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms.
Has ascites. A subject who is clinically stable following treatment for this condition (including therapeutic paracentesis no more than once a week) is eligible.
Has a diagnosis which has been associated with immunodeficiency.
Had prior radiation to more than 50% of all nodal groups.
Is a subject with intra-abdominal abscess.
Is a subject with gastrointestinal obstruction requiring elective or emergency surgery.
Within 4 weeks of the first dose of pembrolizumab had major surgery, excluding minor procedures (e.g. dental work, skin biopsy), celiac plexus block, and biliary stent placement.
Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to study enrolment or within 12 weeks if the investigational agent was immunotherapy.
Has received a live-virus vaccination within 30 days of pembrolizumab start. Seasonal flu vaccines that do not contain live virus are permitted.
Used immunosuppressive drugs over the past 3 months from the enrolment.
A subject on chronic systemic steroids will be excluded from the study. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
Has an active severe infection requiring therapy.
Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation or the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). Marijuana use under medical prescription is permitted according to the Federal and State laws.
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.
Has history of allergy to egg proteins.
Is a woman who is pregnant or breastfeeding.
Has a known history of a second malignancy except if the subject has undergone potentially curative therapy with no evidence of that disease recurrence for 2 years since initiation of that therapy.

Note: The time requirement does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.

Exclusion Criteria for Cohort C and D (Phase II)

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

Has a history of severe autoimmune disease or autoimmune disease requiring active systemic therapy except for thyroiditis or psoriasis.
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 1 week 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 immuno-regulatory receptors or mechanisms.
Cohort D only: Had serious immune related adverse events (Grade 3 or 4) with previous immune checkpoint therapy, that were symptomatic and required prolonged immunosuppression (> 6 weeks).
Had prior allogenic tissue or solid organ transplant.
Has active clinically significant interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids and/or whose pulse oximetry is less than 92% "on room air".
Has symptomatic ascites. A subject who is clinically stable following treatment for this condition (including therapeutic paracentesis no more than once a week) is eligible.
Has known medical history of HIV infection or known medical history of acquired immunodeficiency syndrome (AIDS). HIV testing is not required unless mandated by the local health authority.
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.
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.
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.