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

• ClinicalTrials.gov Identifier: NCT04041310
• Recruitment Status: Recruiting
• First Posted: August 1, 2019
• Last Update Posted: March 3, 2020
• Sponsor: Nouscom SRL
• Information provided by (Responsible Party): Nouscom SRL

Study Description

Brief Summary:

NOUS-209-01 is a multicenter, open-label, multiple cohorts, First In Humans (FIH) 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 based on a heterologous prime/boost regimen composed of the GAd20-209-FSP used for priming and MVA-209-FSP used for boosting in patients with unresectable or metastatic Mismatch Repair Deficient (dMMR) or Microsatellite Instability High (MSI-H) colorectal cancer (CRC), gastric, gastro-esophageal junction (G-E junction) and endometrial tumors in sporadic or hereditary forms of the diseases.

Condition or disease	Intervention/treatment	Phase
Solid Tumor, Adult	Biological: GAd-209-FSP low dose; Biological: MVA-209-FSP low dose; Biological: GAd-209-FSP high dose; Biological: MVA-209-FSP high dose	Phase 1

Detailed Description:

Both FrameShift Peptides (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 patients with unresectable or metastatic dMMR or MSI-H CRC, gastric, or G-E junction tumors. 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).

The study is composed of a Main Study lasting 26 weeks and an Extended Follow-up from week 27 to week 106 of anti-PD-1 checkpoint inhibitor pembrolizumab SOC treatment and further 4 weeks following cessation of pembrolizumab treatment for safety follow-up until week 110.

Main Study:

The Main Study (26 weeks duration) is composed of two sequential cohorts. Cohort A (dose escalation cohort) will determine the recommended phase 2 dose (RP2D) for IP in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with unresectable or metastatic dMMR or MSI-H CRC, gastric, or G-E junction tumors. Cohort B will expand the Cohort A in the same patients' population at the RP2D of IP in combination with pembrolizumab.

Extended Follow-up:

After week 26, treatment with pembrolizumab will continue up to week 106, unless there is documented disease progression (investigators may decide to continue pembrolizumab treatment beyond progression in specific circumstances), unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, or administrative reasons.

At the end of Extended Follow-Up (week 106), or before if pembrolizumab treatment was prematurely discontinued, each subject will be followed for 4 additional weeks (up to week 110) for adverse event monitoring.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

Cohort A - Dose escalation. Patients treated to evaluate safety and tolerability of two heterologous prime/boost vaccine regimen doses (low/low or high/high) in combo with pembrolizumab, and to define Recommended Phase 2 Dose (RP2D).

Cohort B - Dose Expansion. This Cohort will test the RP2D vaccination schedule in combination with pembrolizumab.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, First-In-Human, Multicenter, Open-Label Study of Nous-209 Genetic Vaccine for the Treatment of Microsatellite Unstable Solid Tumors
• Actual Study Start Date: October 21, 2019
• Estimated Primary Completion Date: April 2021
• Estimated Study Completion Date: September 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A. Low dose; Subjects treated with low dose of GAd20-209-FSP prime and MVA-209-FSP boosts to define the RP2D	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 A. High dose; Subjects treated with high dose of GAd20-209-FSP prime and MVA-209-FSP boosts to define the RP2D	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 B. Expansion high dose; Subjects treated with RP2D of GAd20-209-FSP prime and MVA-209-FSP	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

Outcome Measures

Primary Outcome Measures :

1. DLT assessment, in Cohort A [ Time Frame: Within 28 days ]
   Toxicity analyzed within 28-days from the administration of the prime vaccination with GAd20-209-FSP
2. Incidence of Treatment-Emergent Adverse Events, in Cohort A and B. [ Time Frame: 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.

Secondary Outcome Measures :

1. Immunogenicity, in Cohorts A and B [ Time Frame: Through study completion, an average of 2 years ]
   PBMC-derived T-cell responses against vaccine FSPs, as measured by IFN-gamma ELISpot

Other Outcome Measures:

1. Clinical: Objective response (OR) [ Time Frame: Up to 106 weeks ]
   Assessed by tumor imaging using RECIST v1.1
2. Clinical:Time-to-event endpoints including: Time to Tumor Response (TTR) [ Time Frame: Up to 106 weeks ]
   Assessed by the Investigator using RECIST v1.1, and Overall Survival (OS)
3. Clinical: Disease control (DC) [ Time Frame: Up to 106 weeks ]
   Assessed by tumor imaging using RECIST v1.1
4. Clinical:Time-to-event endpoints including: Duration of Response (DR) [ Time Frame: Up to 106 weeks ]
   Assessed by tumor imaging using RECIST v1.1
5. Clinical:Time-to-event endpoints including: Progression-free survival (PFS) [ Time Frame: Up to 106 weeks ]
   Assessed by tumor imaging using RECIST v1.1
6. Clinical: Overall Survival (OS) [ Time Frame: Up to 106 weeks ]
   Assessed by tumor imaging using RECIST v1.1

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

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

   • dMMR/MSI Testing - Patients 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 PCR or NGS based tests.

2. Patients 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).
3. Patients 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).
4. Be ≥18 years of age on day of signing informed consent.
5. Have a life expectancy of at least 6 months.
6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
7. 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. Anyway, the last anti-tumor therapy must have been discontinued at least 4 weeks before vaccination.
8. Have adequate hematological and blood chemistry values
9. Not previously treated with a (licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.
10. 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.
11. 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.
12. Participants with measurable disease per RECIST version 1.1.
13. 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.
14. 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.
15. 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 6.11).
16. Ability to understand and willingness to sign a written Informed Consent form.

Exclusion Criteria:

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

1. 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. Patients with minor well controlled hypothyroidism may be enrolled. Autoimmune diagnoses not listed here must be approved by the medical monitor of the study.
2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients 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.
3. Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs.
4. 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.
5. 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.
6. Has ascites. A subject who is clinically stable following treatment for this condition (including therapeutic paracentesis no more than once a week) is eligible.
7. Has a diagnosis which has been associated with immunodeficiency.
8. Had prior radiation to more than 50% of all nodal groups.
9. Had chemotherapy or radiation within the 4 weeks preceding enrollment.
10. Is a patient with intra-abdominal abscess.
11. Is a patient with gastrointestinal obstruction requiring elective or emergency surgery.
12. 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.
13. 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.
14. Has received a live-virus vaccination within 30 days of pembrolizumab start. Seasonal flu vaccines that do not contain live virus are permitted.
15. Used immunosuppressive drugs over the past 3 months from the enrolment.
16. 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.
17. Has an active infection requiring therapy.
18. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. 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.
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. 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.
23. 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.
24. Has any history of anaphylaxis in reaction to vaccination.
25. Has history of allergy to egg proteins.
26. Is a woman who is pregnant or breastfeeding.
27. Has a known history of a second malignancy except if the patient 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.

Contacts and Locations

Contacts

Contact: Paola Antonini, MD; +39 06 96036299; p.antonini@nouscom.com

Contact: Elisa Scarselli, MD; +39 06 96036299; e.scarselli@nouscom.com

Locations

United States, California

City of Hope Comprehensive Cancer Center; Recruiting

Duarte, California, United States, 91010

Contact: Michael Tajon, PhD, CCRP 626-218-7073 ext 87073 mtajon@coh.org

Principal Investigator: Marwan Fakih, MD

United States, Maryland

Johns Hopkins University; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Davis Liu 410-955-6632

Principal Investigator: Dung Le, MD

United States, Michigan

Barbara Ann Karmanos Cancer Institute; Recruiting

Detroit, Michigan, United States, 48201

Contact: Victoria LaBush 313-576-8411 labushv@karmanos.org

Principal Investigator: Anthony Shields, MD

United States, New York

Northwell Health Cancer Institute; Recruiting

New York, New York, United States, 11042

Contact: Sarah Davis 516-734-7632 sdavis22@northwell.edu

Contact: Edison Sham (516) 734-7632 esham@northwell.edu

Principal Investigator: Wasif Saif

United States, Texas

MD Anderson Cancer Center (MDACC); Recruiting

Houston, Texas, United States, 77030

Contact: Michael J Overman, MD MOverman@mdanderson.org

Principal Investigator: Michael J Overman, MD

Sponsors and Collaborators

Nouscom SRL

Investigators

• Study Director: Paola Antonini, MD; Nouscom SRL

More Information

Additional Information:

Non-clinical results published by D'Alise (Nouscom Srl) et al. in Nature Communications 

• Responsible Party: Nouscom SRL
• ClinicalTrials.gov Identifier: NCT04041310
• Other Study ID Numbers: NOUS-209-01-00; IND #018954 ( Other Identifier: FDA )
• First Posted: August 1, 2019
• Last Update Posted: March 3, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Vaccines; Immunologic Factors; Physiological Effects of Drugs