Immunotherapy in MSI/dMMR Tumors in Perioperative Setting.

Study Overview
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Brief Summary
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This trial is a multicenter, 4-cohort, prospective, Phase II trial conducted in patients with untreated resectable MSI/dMMR carcinomas or EBV+ gastric cancer and aiming to evaluate the safety and the efficacy of ICI (immune checkpoint inhibitor) as neoadjuvant treatment in these patients. We hypothesize that immune checkpoint inhibitors (ICPi) will benefit to MSI/dMMR tumors from the early stages, whatever their anatomical origin. We assume that this neoadjuvant treatment would improve the response rate, providing even high rate of pathological complete responses and prolong patients survival. We anticipated endometrial, colorectal and gastric cancers to be the most frequent recruited and constructed our statistical hypothesis with results in those 3 cancers. However patients with other localized MSI/dMMR tumors could be included.

Detailed Description
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TREATMENT PLAN: Pre-operative pembrolizumab will be administered intravenously (IV) over 30 minutes at the dose of 400 mg according to recent summary of product characteristics (SPC). A single dose will be administered 6 weeks before the planned surgery, as close as possible to inclusion, and whenever possible during standard visit (surgery, anesthesia or other). Surgery will be performed during the 6th week after pembrolizumab injection, as per standard practices. An adjuvant treatment will be administered upon the Investigator decision, depending on the results and tolerance of pre-operative treatment and ability of the patient to receive the treatment regarding his general post-operative condition. STATISTICAL ANALYSIS: A total of 160 patients will be enrolled in this study Sample size was thus evaluated by analogy with an A'Hern's single stage phase II design with P0=25%, P1=50% and 85% power, leading to the inclusion of a maximum of 30 patients by cohort. A sequential Bayesian design will be used to allow continuous monitoring of the primary endpoint and update knowledge gradually. For each cohort, interim analyses are planned after 6-week follow up of the first 10 patients (i.e. after surgery) and then every 10 patients. Early stopping will be recommended if there is a high posterior probability (≥90%) given observed data that the rate of pathological response is lower than 50%. DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING: All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. Serious adverse event (SAE) and Adverse Event of Specific Interest (AESI) reporting will be also paper-based by e-mail and/or Fax. The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

Official Title
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Immunotherapy in MSI/dMMR Tumors in Perioperative Setting.

Conditions
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Localized Resectable Tumor, MSI/dMMR or EBV-positive Gastric Cancers

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria I1. Age ≥ 18 years on the day of signing informed consent. I2. Histologically proven localized non-metastatic tumor included in one of the 4 cohorts: Colon 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 Endometrial carcinoma (stage III) OR Other tumor types (cT2 to cT4 N M0): biliary tract or pancreas adenocarcinoma, small bowel adenocarcinoma (duodenum, jejunum, ileum). I3. MSI/dMMR established by immunohistochemistry (IHC) [MMR protein expression] and polymerase chain reaction (PCR) [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 OR EBV-positive gastric cancers. EBV positivity will be assessed by EBER (EBV-encoded small RNAs) in situ hybridization (ISH) (EBER-PNA EnVision flex probe (Dako)). The intensity of staining (weak, moderate or intense) and the percentage of positive cells will be recorded. Cases showing nuclear staining in at least 5% of tumor cells will be considered positive for EBV infection. I4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1 within 7 days prior to the inclusion. 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/l, platelets ≥ 100 x 109/l, Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 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 patients with total bilirubin >1.5 × ULN), International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants. I6. Covered by a medical/health insurance. I7. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. 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. I9. Signed and dated IRB/IE approved informed consent form. Non-inclusion criteria E1. MSS/pMMR tumors. E2. Metastatic disease (stage IV). E3. HIV positive with CD4 count under 400 cells/mm3 E4. Active Hepatitis B virus (HBV), defined by a positive hepatitis B surface antigen [HBsAg] test prior to inclusion and HBV DNA > 2 000 IU/ml, or Hepatitis C virus (HCV) infection(HCV RNA > 103copy/ml and positive anti-HCV antibodies). 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. E6. Interstitial lung disease. E7. Prior (non-infectious) pneumonitis requiring systemic corticosteroid therapy or current pneumonitis. E8. History of severe hypersensitivity to another monoclonal antibody. E9. Receiving immunosuppressive therapy or having received corticosteroids (in dosing exceeding 10 mg daily of prednisone equivalent) within the last 2 months before inclusion. E10. Active infections. E11. Radiotherapy within the 2 weeks before inclusion. Patients must have recovered from all radiation related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. - Not applicable 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. E13. Known history of active TB (Bacillus Tuberculosis). E14. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. 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. E16. Patient requiring tutorship or curatorship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort Colorectal cancer (CRC)<br>Pembrolizumab prior to surgery | Drug: Pembrolizumab<br>* Administered intravenous (IV)<br>* Other names: MK3475 - Keytruda®;|
| Experimental: Cohort Oesogastric cancer<br>Pembrolizumab prior to surgery | Drug: Pembrolizumab<br>* Administered intravenous (IV)<br>* Other names: MK3475 - Keytruda®;|
| Experimental: Cohort Endometrial cancer<br>Pembrolizumab prior to surgery | Drug: Pembrolizumab<br>* Administered intravenous (IV)<br>* Other names: MK3475 - Keytruda®;|
| Experimental: Cohort Other cancer<br>Pembrolizumab prior to surgery | Drug: Pembrolizumab<br>* Administered intravenous (IV)<br>* Other names: MK3475 - Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete pathological response (pCR) after surgery | A complete pathological response will be defined as 0% viable tumor cells. | 6 weeks after first injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the perioperative treatment | Safety profile, determined using the National Cancer Institute - Common Terminology Criteria for Adverse Event (NCI-CTC AE) grading scale version 5. Adverse events will be described by their intensity and severity | 36 Months (over the whole study) | 
| Rate of surgical complications (post-operative morbidity) | The rate of surgical complications (post-operative morbidity) will be assessed according to modified Clavien Dindo scoring | 1 Month after sugery | 
| Rate of patients with the R0 resection | Percentage of patients with the R0 resection | 36 Months | 
| Major pathological response rate | Percentage of patients with major pathological response (≤ 10% residual viable tumor) | 36 Months | 
| Recurrence-free survival (RFS) | RFS defined as the time from the date of first study treatment administration to the date of first documented recurrence | 36 Months | 
| Overall response rate (ORR) at 4 weeks after the injection of neodjuvant pembrolizumab | Percentage of patients with objective response at 1 month (complete or partial response) after neoadjuvant pembrolizumab, according to RECIST v1.1. | 4 weeks after first study treatment injection | 
| Rate of second cancer in the Lynch syndrom spectrum | Percentage of patients with second cancer | 36 Months | 
| The overall survival (OS) | OS, defined from the date of first study treatment administration to the date of death due to any cause. | From 36 months | 
| Progression-free survival (PFS) after recurrence | PFS, defined from the date of first documented recurrence to the date of documented progression. | 36 months | 
| Quality of life (QoL) | QoL, assessed using the EORTC QLQ-C30 | Baseline, before surgery and at 5 months post inclusion | 
| The prognostic value of lung immune prognostic index (LIPI) |  | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, MSI/dMMR status, EBV positive gastric cancers, Pembrolizumab, Immunotherapy, Phase II, Neoadjuvant treatment