Genetic vaccine for the treatment of microsatellite unstable solid tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Nouscom S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 May 2022 → ongoing

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Nouscom S.r.l.

External identifiers

EU CT number

2024-514723-42-00

EudraCT number

2021-002823-40

ClinicalTrials.gov

NCT04041310

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

For Phase IIa: To assess preliminary evidence of anti-tumor activity based on RECIST v1.1 of the vaccination regimen plus pembrolizumab in terms of ORR.
For Phase IIb (Cohorts C and D): To assess preliminary evidence of anti-tumor activity based on RECIST v1.1 of the vaccination regimen plus pembrolizumab in terms of ORR, based on Simon 2-stage design.

Secondary objectives 1

1. For Phase IIa: • Safety: To evaluate the overall safety and tolerability of the RP2D of GAd20-209-FSP and MVA-209-FSP vaccination regimen plus pembrolizumab. • Efficacy: To assess additional preliminary evidence of anti-tumor activity based on RECIST v1.1 of the vaccination regimen plus pembrolizumab in terms of: o Best Overall Response (BOR); o Duration of Response (DoR) and Progression-Free survival (PFS) at 6, 12, 18, and 24 months. For Phase IIb (Cohorts C and D): • Safety: To evaluate the overall safety and tolerability of the RP2D of GAd20-209-FSP and MVA-209-FSP vaccination regimen plus pembrolizumab. • Efficacy: To assess additional preliminary evidence of anti-tumor activity based on RECIST v1.1 of the vaccination regimen plus pembrolizumab in terms of: o Best Overall Response (BOR), o Duration of Response (DoR) and Progression-Free survival (PFS) at 6 , 12, 18, and 24 months.

Conditions and MedDRA coding

Locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or dMMR CRC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Have the ability to comprehend and willingness to provide written informed consent (ICF) for the study.
2. If participating in translational research 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. Furthermore, optionally agree to have another biopsy taken on treatment 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.
3. Have measurable disease per RECIST version 1.1.
4. Patients 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.
5. Females: not be pregnant, not breastfeed, and must have at least one of the following conditions that apply: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly effective contraceptive methods as outlined in Appendix 7 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.
6. Fertile male patients: agree to use a contraceptive 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.
7. 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 based on previous diagnosis for dMMR/MSI status. dMMR/MSI status diagnosis should be performed locally, by IHC or NGS or PCR based tests that are certified per local requirements.
8. For Cohort C (Phase II):Patients 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. Patients may have received prior adjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to Study Day 1. For Cohort D (Phase IIb): Patients 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.
9. Be ≥18 years of age on day of signing informed consent.
10. Have a life expectancy of at least 6 months.
11. Have a performance status of 0/1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 2 or less (except alopecia). If patient received major surgery or radiation therapy they must have recovered from the toxicity and/or complications from the intervention.
13. Have adequate organ function (for Cohort C) and adequate hematological and blood chemistry values for Phase II (for Cohort D) as defined in the following tables (Table 1: Adequate Organ Function Laboratory Values). Specimens must be collected within 10 days prior to the start of the study. If any hematological or chemistry values are outside the specified range during the initial screening, rescreening process may be conducted to reassess and ensure compliance with the adequate organ function criteria as outlines in Table 1.
14. For Cohort C (Phase II): Not have been previously treated with a (licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.
15. For Cohort D (Phase IIb): May have progressed on additional approved therapy.

Exclusion criteria 13

1. For Phase IIb: 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.
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 14 days prior to pembrolizumab.
3. Is expected to require any form of systemic or localized antineoplastic therapy while on study other than the study drugs. Phase IIa and Cohort C only: Had prior adjuvant treatment with an anti-PD-1, or PD-L1 or PDL2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms.
4. Cohort D only: discontinued prior therapy with a checkpoint inhibitor due to Grade 3, or higher, treatment-related toxicities.
5. Had prior allogenic tissue or solid organ transplant.
6. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
7. Has known medical 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: a.Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening b.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 c) 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).
8. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
9. 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. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Note: A one-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) forto non-CNS disease.
10. 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.
11. 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. Administration of killed vaccines are allowed.
12. Has an active severe infection requiring therapy.
13. Has active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (i.e., positive hepatitis B surface antigen [HBsAg]). Patients with negative HBsAg and positive total hepatitis B core antibody may be included if HBV DNA is undetectable at the time of screening. Patients who are positive for HCV antibody are eligible only if polymerase chain reaction test is negative for HCV RNA. Patients 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. For Phase IIa: ORR assessed by standard RECIST v 1.1 criteria For Phase II b (Cohorts C and D): ORR assessed by standard RECIST v 1.1 criteria

Secondary endpoints 1

1. For Phase IIa Safety and tolerability: AEs as characterized by type, severity (graded by the NCI CTCAE v.5.0), timing, seriousness, and relationship to study treatments. Efficacy assessed by standard RECIST v1.1 criteria: BOR,DoR, and PFS at 6, 12, 18, and 24 months. For Phase IIb (Cohorts C and D) Safety and tolerability: AEs as characterized by type, severity (graded by the NCI CTCAE v.5.0), timing, seriousness, and relationship to study treatments. Efficacy assessed by standard RECIST v

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Nouscom S.r.l.

Sponsor organisation

Nouscom S.r.l.

Address

Via Di Castel Romano 100

City

Rome

Postcode

00128

Country

Italy

Scientific contact point

Organisation

Nouscom S.r.l.

Contact name

Justine Lees

Public contact point

Organisation

Nouscom S.r.l.

Contact name

Clinical trial information

Third parties 4

Locations

3 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications