| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or dMMR CRC who are eligible for anti-PD-1 1st line of treatment (Cohort C) and/or Subjects with locally advanced unresectable or metastatic, microsatellite instability high (MSI-H) or dMMR CRC who have had radiographic progression (PD) after having a best response of stable disease (SD) or better on/after anti-PD1 treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Microsatellite unstable solid tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 Best Overall Response (BOR), 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 Best Overall Response (BOR), Duration of Response (DoR) and Progression-Free survival (PFS) at 6, 12, 18 and 24 months.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Have the ability to comprehend and willingness to provide written
informed consent (ICF) for the study.
2.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.
3.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.
4. For Cohort D (Phase IIb): May have progressed on additional approved therapy.
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 0/1 on the Eastern Cooperative Oncology
Group (ECOG) Performance Status.
7.Have resolution of toxic effect(s) of the most recent prior
chemotherapy to Grade 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.
8.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.
9.For Cohort C (Phase II): Not have been previously treated with a
(licensed or experimental) anti-PD-1 or anti-PD-L1 checkpoint inhibitor.
10. 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.
11.Have measurable disease per RECIST version 1.1.
12.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.
13.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 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.
14. 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. |
|
| E.4 | Principal exclusion criteria |
For Phase IIb:
1.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. 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 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 PD-L2 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. 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.
14.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.
15.Has any history of anaphylaxis in reaction to a vaccination.
16.Is a woman who is pregnant or breastfeeding.
17.Any condition in the judgment of the Investigator, which makes the
patient unsuitable for study participation; including psychological
conditions.
18. Has known hypersensitivity to pembrolizumab or to components of the Nous-209 study therapy or its analogues (including a known history of allergy to egg proteins).
Please see the rest of Exclusion criteria in Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For Phase IIa: ORR assessed by standard RECIST v 1.1 criteria
For Phase IIb (Cohort C and D): ORR assessed by standard RECIST v 1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Phase IIa: Endpoint will be measured at 24 months
For Phase IIb (Cohort C and D): Endpoint will be measured at 24 months |
|
| E.5.2 | Secondary end point(s) |
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 v1.1 criteria: BOR, DoR, and PFS at 6, 12, 18 and 24 months.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6 months, 12 months, 18 months and 24 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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