Nous-209 Genetic Vaccine for the Treatment of Microsatellite Unstable Solid Tumors
Study Details
Study Description
Brief Summary
Ref: Protocol v5.0, dated 1Jul2021. NOUS-209-01 is a multicenter, open-label, multiple cohorts, clinical study, designed to evaluate safety, tolerability, and immunogenicity, and to detect any preliminary evidence of anti-tumor activity of Nous-209 genetic polyvalent vaccine plus pembrolizumab combination therapy in adult subjects with unresectable or metastatic deficient mismatch repair (dMMR) or MSI-H CRC, gastric, or gastro-esophageal junction (G-E junction) tumors. Nous-209 is based on a heterologous prime/boost regimen composed of the Great Ape Adenovirus GAd20-209-FSP used for priming and Modified Vaccinia virus Ankara MVA-209-FSP used for boosting. The Phase I portion of the study is a first-in-human (FIH) clinical study with a primary objective to elucidate the safety and tolerability of Nous-209 in addition to establishing the recommended Phase 2 dose (RP2D), whereas the Phase IIa was introduced to assess efficacy as the primary objective. The Phase I stage of the study has been conducted in US; the Phase II will be conducted in US and in EU (pending authorization).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Ref: Protocol v5.0, dated 1Jul2021. Both Frame Shift Peptide (FSP) neoantigen-encoding genetic vaccines are administered intramuscularly using 1 prime with the GAd20-209-FSP and 3 boosts with MVA-209-FSP in combination with the licensed programmed death receptor-1 (PD-1)-blocking antibody pembrolizumab in adult subjects with unresectable or metastatic Mismatch Repair Deficient (dMMR) or MSI-H colorectal cancer (CRC), gastric, or G-E junction tumors. In Phase I, GAd20-209-FSP prime will be administered on the day of 2nd pembrolizumab infusion (week 4); MVA-209-FSP boosts will be administered on the day of 3rd, 4th and 5th pembrolizumab infusion (weeks 7 and 10 and 13). In Phase IIa, GAd20-209-FSP prime will be administered on the same day as the 1st pembrolizumab infusion (day 1, week 1); MVA-209-FSP boosts will be administered on the day of 2nd, 3rd, and 4th pembrolizumab infusion (weeks 4 and 7 and 10).
The study is composed of a Phase I divided in two parts and a Phase IIa, as described below :
Phase I:
Part 1- Main Study of 26 weeks duration.
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Cohort A - Dose escalation Cohort of Nous-209 vaccine plus pembrolizumab combination therapy in adult subjects with unresectable or metastatic deficient mismatch repair (dMMR) or MSI-H CRC, gastric, or gastro-esophageal junction (G-E junction) tumors;
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Cohort B - Expansion Cohort at RP2D of Nous-209 vaccine plus pembrolizumab combination therapy in adult subjects with unresectable or metastatic dMMR or MSI-H CRC, gastric, or G-E junction tumors.
Part 2 - Extended Follow-up from week 27 to week 110. - Cohorts A and B.
Phase IIa:
Expansion at RP2D of Nous-209 vaccine plus pembrolizumab combination therapy in adult subjects in the following study population:
- Cohort C - Subjects with locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or dMMR CRC who are eligible for anti-PD-1 1st line of treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort A - Dose-escalation Phase I. Part 1. Dose escalation cohort. Subjects treated with low dose or with high dose of GAd20-209-FSP prime and MVA-209-FSP boosts to define the RP2D, in combination with pembrolizumab. Phase I. Part 2 - Extended Follow-up from week 27 to week 110. Subjects with unresectable or metastatic deficient mismatch repair (dMMR) or MSI-H CRC, gastric, or gastro-esophageal junction (G-E junction) tumors. |
Biological: GAd-209-FSP low dose
GAd20-209-FSP IM vaccine, low dose
Biological: MVA-209-FSP low dose
MVA-209-FSP IM vaccine, low dose
|
| Experimental: Cohort B - Expansion Cohort Phase I Phase I. Part 1. Expansion cohort at RP2D. Subjects treated with RP2D dose of GAd20-209-FSP prime and MVA-209-FSP boosts, in combination with pembrolizumab. Phase I. Part 2 - Extended Follow-up from week 27 to week 110. Subjects with unresectable or metastatic dMMR or MSI-H CRC, gastric, or G-E junction tumors. |
Biological: GAd-209-FSP high dose
GAd20-209-FSP IM vaccine, high dose
Biological: MVA-209-FSP high dose
MVA-209-FSP IM vaccine, high dose
|
| Experimental: Cohort C - Expansion cohort Phase IIa Phase IIa. Expansion cohort at RP2D. Subjects treated with RP2D of GAd20-209-FSP prime and MVA-209-FSP, in combination with pembrolizumab. Subjects with locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or dMMR CRC who eligible for anti-PD-1 1st line treatment. |
Biological: GAd20-209-FSP, RP2D
GAd20-209-FSP IM vaccine, RP2D
Biological: MVA-209-FSP, RP2D
MVA-209-FSP IM vaccine, RP2D
|
Outcome Measures
Primary Outcome Measures
- Toxicity (DLT assessment), in Phase I, Cohort A [Within 28 days]
Toxicity analyzed within 28-days from the administration of the prime vaccination with GAd20-209-FSP
- Incidence of Treatment-Emergent Adverse Events, in Phase I, Cohort A and B. [Up to 110 weeks]
AEs as characterized by type, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.5.0), timing, seriousness, and relationship to study treatments.
- Overall Response Rate (ORR) at 12 months, in Phase IIa (Cohort C). [12 months]
Assessed using RECIST v1.1
Secondary Outcome Measures
- Immunogenicity (T cell responses against vaccine FSPs) in Phase I, Cohorts A and B [Through study completion, an average of 2 years]
PBMC-derived T cell responses against vaccine FSPs, as measured by IFN-gamma ELISpot
- Safety and tolerability (local and systemic AEs), in Phase IIa (Cohort C) [Up to 18 months]
AEs as characterized by type, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.5.0), timing, seriousness, and relationship to study treatments. Assessed by standard using RECIST v1.1 criteria at 6, 12 and 18 months.
Other Outcome Measures
- Clinical: Overall Response Rate (ORR), in Phase I, Cohort A and B [Phase I Main Study and Extended follow-up. Up to 110 weeks]
Assessed by tumor imaging using RECIST v1.1
- Clinical: Disease Control Rate (DCR), in Phase I, Cohort A and B [Phase I Main Study and Extended follow-up. Up to 110 weeks]
Assessed by tumor imaging using RECIST v1.1
- Clinical: Time to Tumor Response (TTR), Phase I Main Study and Extended follow-up. [Phase I Main Study and Extended follow-up. Up to 110 weeks.]
Assessed by the Investigator using RECIST v1.1, and Overall Survival (OS)
- Clinical: Duration of Response (DR), Phase I Main Study and Extended follow-up. [Up to 110 weeks]
Assessed by tumor imaging using RECIST v1.1
- Clinical: Progression-free survival (PFS), Phase I Main Study and Extended follow-up. [Up to 110 weeks]
Assessed by tumor imaging using RECIST v1.1
- Clinical: Overall Survival (OS), Phase I Main Study and Extended follow-up. [Up to 110 weeks]
Assessed by tumor imaging using RECIST v1.1
- Clinical: Overall Survival (OS), Phase IIa (Cohort C). [Up to 18 months]
Assessed by tumor imaging using RECIST v1.1
Eligibility Criteria
Criteria
Inclusion Criteria for Cohorts A and B (Phase I):
In order to be eligible, the subject must:
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Have the ability to comprehend and willingness to provide written informed consent (ICF) for the study.
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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.
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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.
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Be ≥18 years of age on day of signing informed consent.
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Have a life expectancy of at least 6 months.
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Have a performance status of 0 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
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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.
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Have adequate hematological and blood chemistry values for Phase 2a.
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Not previously treated with a (licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.
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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.
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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.
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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.
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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).
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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).
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Ability to understand and willingness to sign a written Informed Consent form.
Subject Inclusion Criteria for Cohort C (Phase IIa)
In order to be eligible, the subject must:
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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.
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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.
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Be ≥18 years of age on day of signing informed consent.
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Have a life expectancy of at least 6 months.
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Have a performance status of 0 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
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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.
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Have adequate hematological and blood chemistry values for Phase 2a.
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Not be previously treated with a (licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.
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Only at selected US 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) formalin-fixed paraffin-embedded (FFPE) specimen from locations not radiated prior to biopsy can be accepted.
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Have measurable disease per RECIST version 1.1.
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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.
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Females: not be pregnant [see Appendix 6], not breastfeed, and must have at least one of the following conditions that apply:
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Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR
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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:
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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.
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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.
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Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs.
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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.
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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.
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Has ascites. A subject who is clinically stable following treatment for this condition (including therapeutic paracentesis no more than once a week) is eligible.
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Has a diagnosis which has been associated with immunodeficiency.
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Had prior radiation to more than 50% of all nodal groups.
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Is a subject with intra-abdominal abscess.
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Is a subject with gastrointestinal obstruction requiring elective or emergency surgery.
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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.
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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.
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Has received a live-virus vaccination within 30 days of pembrolizumab start. Seasonal flu vaccines that do not contain live virus are permitted.
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Used immunosuppressive drugs over the past 3 months from the enrolment.
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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.
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Has an active severe infection requiring therapy.
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Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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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.
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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.
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Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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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.
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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.
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Has any history of anaphylaxis in reaction to a vaccination.
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Has history of allergy to egg proteins.
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Is a woman who is pregnant or breastfeeding.
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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 (Phase IIa)
The subject must be excluded from participating in if he/she:
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Has a history of severe autoimmune disease or autoimmune disease requiring active systemic therapy except for thyroiditis or psoriasis.
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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.
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Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs. 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.
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Had prior allogenic tissue or solid organ transplant.
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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".
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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.
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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.
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Had prior radiotherapy within 2 weeks of enrolment, or within 4 weeks of enrolment 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.
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Has immunosuppression implying the continued use of systemic (at prednisone dose equivalent of >10 mg) or topical steroids at or near the planned i.m. 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.
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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, please contact the study Medical Monitor.
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Has an active severe infection requiring therapy.
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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 polymerase chain reaction 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.
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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.
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Has any history of anaphylaxis in reaction to a vaccination.
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Is a woman who is pregnant or breastfeeding.
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Any condition in the judgment of the Investigator, which makes the subject unsuitable for study participation; including psychological conditions.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 2 | Johns Hopkins University | Baltimore | Maryland | United States | 21287 |
| 3 | Barbara Ann Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
| 4 | Washington University School of Medicine, Division of Oncology | Saint Louis | Missouri | United States | 63110 |
| 5 | Roswell Park Comprehensive Cancer Center | Buffalo | New York | United States | 14203 |
| 6 | NYU Langone Medical Center | New York | New York | United States | 10016 |
| 7 | Weill Cornell Medicine / New York-Presbyterian Hospital | New York | New York | United States | 10021 |
| 8 | MD Anderson Cancer Center (MDACC) | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Nouscom SRL
Investigators
- Study Director: Patricia Delaite, MD, Nouscom SRL
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- NOUS-209-01
- IND #018954
- 2021-002823-40