MSI/dMMR tumors in perioperative setting
- Conditions
- MSI/dMMR tumors or EBV+ gastric cancer
- Registration Number
- 2024-518127-30-00
- Lead Sponsor
- Centre Leon Berard
- Brief Summary
To evaluate the efficacy of pembrolizumab MK-3475 in patients with untreated localized non-metastatic MSI/dMMR carcinomas or EBV+ gastric cancer, independently of their anatomical origin.
- Detailed Description
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). Until four doses 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 the last pembrolizumab injection, as per standard practices.
An adjuvant treatment will be administered upon the Investigator decision, depending on the protocol: 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 240 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.
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.
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 240
I1. Age ≥ 18 years on the day of signing informed consent.
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 - Endometrial carcinoma (stage III) OR[Closed to inclusions] - Other tumor types (cT2 to cT4, N, M0) : small bowel
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. 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 tumour cells will be considered positive for EBV infection. [Closed to inclusions]
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, 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. or cells will be considered positive for EBV infection.
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.
E1. MSS/pMMR tumors.
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.
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.
E17. Ongoing anti-cancer treatment for another cancer (to be discussed with the coordinator in case of hormone therapy).
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
E19. Patient hospitalized at the moment of inclusion and treatment initiation (palliative care unit, retirement home … are considered as hospitals).
E2. Metastatic disease (stage IV).
E20. Recent hemorrhage (in the month before inclusion).
E3. HIV positive with CD4 count under 400 cells/mm3 .
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).
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method 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). 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).
- Secondary Outcome Measures
Name Time Method Safety profile Safety profile
Rate of surgical complications Rate of surgical complications
Percentage of patients with R0 resection Percentage of patients with R0 resection
Percentage of patients with major pathological response Percentage of patients with major pathological response
RFS RFS
Percentage of patients with objective response 4, 10, 16 and 21 weeks Percentage of patients with objective response 4, 10, 16 and 21 weeks
Percentage of patients with second cancer in the Lynch syndrome spectrum Percentage of patients with second cancer in the Lynch syndrome spectrum
OS OS
PFS PFS
QoL QoL
Association between LIPI score and the response to treatment Association between LIPI score and the response to treatment
In the subgroup of patients without surgery: Progression free survival (PFS), In the subgroup of patients without surgery: Progression free survival (PFS),
Trial Locations
- Locations (24)
Institut Godinot
🇫🇷Reims, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Centre Francois Baclesse
🇫🇷Caen Cedex 5, France
Institut Mutualiste Montsouris
🇫🇷Paris, France
Centre Hospitalier Universitaire De Nantes
🇫🇷Nantes, France
Centre Leon Berard
🇫🇷Lyon, France
University Hospital Of Clermont-Ferrand
🇫🇷Clermont-Ferrand, France
Centr Georges Francois Leclerc
🇫🇷Dijon, France
Hôpital de la Timone
🇫🇷Marseille, France
Assistance Publique Hopitaux De Paris
🇫🇷Le Kremlin-Bicetre, France
Scroll for more (14 remaining)Institut Godinot🇫🇷Reims, FranceDamien BOTSENSite contact0326504438damien.botsen@reims.unicancer.fr