| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| oeso-gastric adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| oeso-gastric adenocarcinoma |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001150 |
| E.1.2 | Term | Adenocarcinoma gastric |
| 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 |
| To evaluate the rate of complete pathologic response rate (cPRR) with nivolumab and ipilimumab combination in patients with MSI and/or dMMR localized oeso-gastric cancer |
|
| E.2.2 | Secondary objectives of the trial |
- To assess disease-free survival (DFS),
- To assess overall survival (OS),
- To evaluate the safety (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0),
- To evaluate the efficacy of nivolumab and ipilimumab regimen according to selected tumor - biomarkers:
• MMR proteins status (Lynch versus sporadic),
• BRAF gene mutational status and/or MLH1 gene epigenetic status,
• PD-1 and PD-L1 expression (combined positive score [CPS] in addition to tumor proportion score [TPS]), (≥1% and ≥5% versus no expression),
• CD3+, CD8+, and FOXP3 (expression versus no expression),
- To evaluate whetherPD-L1, PD-L2, PD-1, (-4, TIM-3, LAG-3, GAL9, IDO, expression could be predictive of patients’ response to these molecules,
- Blood assessment for ctDNA, MSI status, and CD4+ T cells,
- To investigate whether the gut microbiota composition is predictive of toxicity and efficacy of nivolumab and/or ipilimumab treatment.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent,
2. Age ≥18 years,
3. Histologically proven non-metastatic gastric adenocarcinoma or of the oeso-gastric junction T2 to T4, Nx, M0 after thoraco-abdomino-pelvic computed tomography (CT) and/or echo-endoscopy if necessary,
4. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study,
5. dMMR DNA (protein expression by immunohistochemistry [ICH] and/or MSI by polymerase chain reaction [PCR]),
MMR and/or MSI tumors should be assessed per local guidelines: ICH with two (anti-MLH1 and anti-MSH2 or anti-MSH6, and anti-PMS2) or four antibodies (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) and/or PCR (with PROMEGA: BAT-25, BAT-26, NR-21, NR-24, and NR-27) by the investigators prior to screening,
Extinct MLH1 (+/- PMS2), MSH2 (+/- MSH6), MSH6, or PMS2 alone protein expression by IHC (dMMR), and/or tumor with ≥ 2 instable MSI-H markers on PCR: BAT25, BAT26, NR21, NR24, and NR27 (pentaplex panel is recommended),
Agreement of the SPONSOR (GERCOR) is mandatory to include the patient (the patient’s file will be verified to confirm a dMMR/MSI-H status before inclusion [an anonymized fax] and confirmation of a patient’s allocation will be sent by mail to the Investigator within 24h),
6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1,
7. Hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥9 g/dL,
8. Adequate renal function: serum creatinine level <120 µM, clearance > 50ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),
9. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase <5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3.0 x ULN,
10. No prior therapy for localized oeso-gastric cancer,
11. Radiological tumor assessment within 21 days before first treatment according to RECIST version 1.1 by Chest Abdomen and Pelvis CT,
12. For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug,
13. Men and women are required to use adequate birth control during the study (when applicable),
Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use a highly effective method of birth control (i.e., pregnancy rate of less than 1% per year) during the period of treatment and during 5 and 7 months, woman and men, respectively, from the last treatment administration. Men must refrain from donating sperm during this same period,
Contraceptive methods that result in a low failure rate when used consistently and correctly include methods such as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), some intrauterine devices, intrauterine hormone-releasing stem, true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant), bilateral tubal occlusion, or a female partner who is not of childbearing potential or a male partner who has had a vasectomy. Women and female partners using hormonal contraceptive must also use a barrier method i.e. condom or occlusive cap (diaphragm or cervical/vault caps),
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus),
14. Subject willing to comply to provide primary tumor tissue (archival or fresh biopsy specimen), including possible pre-treatment biopsy for PD-L1 expression analysis and other biomarker correlative studies
15. Registration in a National Health Care System (PUMa - Protection Universelle Maladie included), |
|
| E.4 | Principal exclusion criteria |
1. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
2. Treatment with any investigational medicinal product within 28 days prior to study entry,
3. Major surgical procedure within 4 weeks prior to initiation of study treatment,
4. Other serious and uncontrolled non-malignant disease (including active infection),
5. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years,
6. Metastases (M stage disease) whatever the location,
7. Pregnant or breastfeeding women,
8. Human immunodeficiency virus (HIV),
9. Active hepatitis B virus (HBV, defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C virus (HCV).
Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible.
Note: Patients positive for HCV antibody are eligible only if PCR testing is negative for HCV RNA.
Non-eligible to immunotherapy:
10. History of autoimmune disease including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis,
Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest imaging,
12. Administration of a live, attenuated vaccine within 4 weeks prior to start of treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study,
13. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents,
14. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
15. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including, but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to start of maintenance treatment, or requirement for systemic immunosuppressive medications during the remainder of the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled into the study after approval of the Medical Monitor. Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses including doses >10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete pathological response rate (cPRR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| cPRR will be defined as complete tumor disappearance of tumor in the low esophagus or the stomach (from 1/3 inferior of the oesophagus to pylorus) after-surgery examination |
|
| E.5.2 | Secondary end point(s) |
- DFS,
- OS and safety (NCI CTCAE v5.0),
- IHC evaluation of MMR proteins followed by tumor BRAF analysis (germline mutation) and/or MLH1 promoter hypermethylation analysis (somatic mutation) when MLH1 protein is absent (Lynch versus sporadic cases testing),
- PD-1 and PD-L1 expression evaluation (CPS in addition to TPS), (PD-L1 [+] expression cut-off ≥1% or ≥5%),
- CD3, CD8, FOXP3 expression evaluation,
- Blood samples : Evaluation of the potential role of immune checkpoint inhibitors: PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, GAL9, and IDO using nanostring technology and IHC as predictive markers of patients’ response to treatment,
- blood samples : ctDNA evolution during treatment, MSI status and CD4+ T cells in blood,
- Microbiota analysis.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DFS is defined as the time from the date of starting treatment to local recurrence and/or metastases or death irrespective of cause and censored at the date of last contact.
- OS is defined as time between the date of the first dose of study treatment and the death date.
- AEs : at every visit during treatment and at 3 months after treatment ends(NCI-CTCAE version 5.0)
- MSI and/or dMMR had to be confirmed with an archival or fresh tumor FFPET block from the primary tumor obtained at the time of the initial diagnosis
- Blood Samples : at baseline, C3D1 and C6D1 of neoadjuvant treatment, at C1D1 after surgery, and at the end of treatment visit
Fecal sample: At baseline and 12 weeks. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| maximum 5 years (60 months) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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