Pembrolizumab for Microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) tumours | Epstein–Barr virus (EBV)-positive gastric cancer

Inclusion criteria

• {"criterion_text":"- I1. Age ≥ 18 years on the day of signing informed consent.\n- I2. Histologically proven localized non-metastatic tumor included in one of the following cohorts: - Colorectal or rectal Cancer (cT3/T4 N0 M0 ou cT N+ M0) OR - Oesogastric (gastric, gastro-oesophageal or oesophageal) cancer (cT2 to cT4, N, M0) OR - Other tumor types (cT2 to cT4, N, M0) : small bowel adenocarcinoma (duodenum, jejunum, ileum)\n- I3. MSI/dMMR established by immunohistochemistry (IHC) [MMR protein expression] and polymerase chain reaction (PCR) (or NextGeneration Sequencing (NGS)) [both techniques are required] and validated by coordinator's team. MMR and/or MSI tumors will be assessed using IHC with four antibodies (anti-MLH1, anti-MSH2, anti-MSH6 and anti-PMS2) and PCR (pentaplex panel is recommended: BAT-25, BAT-26, NR-21, NR-24, and NR-27) prior to screening. Loss of MLH1 and PMS2 / or MSH2 and MSH6 / or MSH6 alone / or PMS2 alone protein staining by IHC indicates dMMR, and tumor with ≥ 2 unstable markers analyzed on PCR proves MSI/dMMR. NGS will be accepted instead of PCR analysis.\n- I4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1 within 7 days prior to the inclusion.\n- I5. Adequate bone-marrow, hepatic, and renal functions, within 10 days prior to the start of study treatment with: - Hemoglobin ≥ 9 g/dl or ≥ 5.6 mmol/l, neutrophils ≥ 1.0 x 109, platelets ≥ 100 x 109, - Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 30 ml/min/1.73m² using either MDRD or CKD-EPI formula, - AST and ALT ≤ 3 x ULN, total bilirubin ≤ 1.5 ULN (or direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN), - INR or PT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.\n- I6. Covered by a medical/health insurance.\n- I7. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.\n- I8. Patients of childbearing potential accepting to use effective contraceptive measures or abstain from heterosexual activity, for the course of the study through 4 months after the last dose of pembrolizumab MK-3475 adjuvant treatment or 6 months after adjuvant chemotherapy or being surgically sterile. Refer to Appendix 1 for approved methods of contraception.\n- I9. Signed and dated IRB/IE approved informed consent form."}

Exclusion criteria

• {"criterion_text":"- E1. MSS/pMMR tumors.\n- E19. Patient hospitalized at the moment of inclusion and treatment initiation (palliative care unit, retirement home … are considered as hospitals).\n- E2. Metastatic disease (stage IV).\n- E20. Recent hemorrhage (in the month before inclusion).\n- E3. HIV positive with CD4 count under 400 cells/mm3 .\n- E4. Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive and/or detectable HBV DNA) or Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection).\n- E5. Active systemic autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin) is not considered a form of systemic treatment and is allowed.\n- E6. Interstitial lung disease.\n- E7. Prior (non-infectious) pneumonitis requiring systemic corticosteroid therapy or current pneumonitis.\n- E8. History of severe hypersensitivity to another monoclonal antibody.\n- E9. Receiving immunosuppressive therapy or having received corticosteroids (in dosing exceeding 10 mg daily of prednisone equivalent) within the last 2 months before inclusion.\n- E10. Active infections.\n- E12. Live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed\n- E13. Known history of active TB (Bacillus Tuberculosis).\n- E14. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.\n- E15. Pregnant or breastfeeding woman or patient expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 4 months after the last dose of study treatment.\n- E16. Patient requiring tutorship or curatorship.\n- E17. Ongoing anti-cancer treatment for another cancer (to be discussed with the coordinator in case of hormone therapy).\n- E18. Prior history of other malignancies (except for HNPCC or Lynch syndrome-related cancers) unless the subjects has been free of the disease for at least 2 years"}

Primary endpoints

• {"endpoint_text":"- The primary endpoint will be the rate of complete pathological response (pCR) after surgery according to local pathological evaluation. A complete pathological response will be defined as 0% viable tumor cells in tumor or nodal site (ypT0N0).","definition_or_measurement_approach":"Complete pathological response defined as 0% viable tumor cells in tumour or nodal site (ypT0N0) assessed by local pathological evaluation after surgery."}

Secondary endpoints

• {"endpoint_text":"- Safety profile","definition_or_measurement_approach":"Safety assessed according to NCI CTCAE v5 (perioperative treatment safety as described in secondary objectives)."}
• {"endpoint_text":"- Rate of surgical complications","definition_or_measurement_approach":"Post-operative morbidity assessed according to modified Clavien–Dindo scoring (as specified in secondary objectives)."}
• {"endpoint_text":"- Percentage of patients with R0 resection","definition_or_measurement_approach":"R0 resection rate assessed by surgical/pathological reports (no residual tumour at resection margins)."}
• {"endpoint_text":"- Percentage of patients with major pathological response","definition_or_measurement_approach":"Major pathological response defined as ≤ 10% residual viable tumor (as in secondary objectives)."}
• {"endpoint_text":"- RFS","definition_or_measurement_approach":"Recurrence-free survival measured from inclusion/registration to documented recurrence or death (definition provided as RFS in objectives)."}
• {"endpoint_text":"- Percentage of patients with objective response 4, 10, 16 and 21 weeks","definition_or_measurement_approach":"Overall response rate (ORR) assessed at 4, 10, 16 and 21 weeks after pembrolizumab initiation using CT-scan and/or endoscopy and/or 18FDG PET-scan (weeks 5-6, 11-12, 17-18 and 22-24 as per objectives)."}
• {"endpoint_text":"- Percentage of patients with second cancer in the Lynch syndrome spectrum","definition_or_measurement_approach":"Rate of second primary cancers within Lynch syndrome spectrum as recorded during follow-up."}
• {"endpoint_text":"- OS","definition_or_measurement_approach":"Overall survival measured from inclusion/registration to death from any cause."}
• {"endpoint_text":"- PFS","definition_or_measurement_approach":"Progression-free survival after recurrence (as specified in objectives) measured using standard radiological/clinical criteria."}
• {"endpoint_text":"- QoL","definition_or_measurement_approach":"Quality of life measured using patient-reported QoL instruments (details in protocol/patient-facing documents)."}
• {"endpoint_text":"- Association between LIPI score and the response to treatment","definition_or_measurement_approach":"Assessment of prognostic value of Lung Immune Prognostic Index (LIPI) in relation to treatment response."}
• {"endpoint_text":"- In the subgroup of patients without surgery: Progression free survival (PFS),","definition_or_measurement_approach":"PFS for patients not undergoing surgery measured from inclusion to progression or death."}

France

Earliest CTIS Part Ii Submission Date

28-10-2024

Latest Decision Or Authorization Date

13-03-2026

Processing Time Days

501

Number Of Sites

18

Number Of Participants

240

Primary sponsor

Full Name

Centre Leon Berard

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France