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.
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 120 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.
INCLUSION CRITERIA
I1. Age ≥18 years on the day of signing informed consent.
I2. Localized resectable tumor included in one of the 4 cohorts:
- Colorectal Cancer OR
- Oesogastric cancer OR
- Endometrial carcinoma OR
- Other tumor types (miscellaneous cohort).
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 among 5 microsatellite markers analyzed on PCR (BAT25, BAT26, NR21,
NR24, and NR27) 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 tumour 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 upperl limit of normal (ULN) OR Calculated creatinine clearance ≥
50 ml/min/1.73m² using either the MDRD or CKD-EPI formula,
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 x ULN, total
bilirubin ≤ 1.5 x ULN (or direct bilirubin ≤ ULN for patients with total bilirubin
levels >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.
EXCLUSION CRITERIA:
E1. MSS/pMMR tumors.
E2. Metastatic disease.
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 or hepatitis C virus (HCV) 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.
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).
