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    Summary
    EudraCT Number:2020-004957-62
    Sponsor's Protocol Code Number:ET20-093
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-03-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-004957-62
    A.3Full title of the trial
    Immunotherapy in MSI/dMMR Tumors in perioperative setting
    Immunothérapie en péri-opératoire dans les tumeurs MSI/dMMR
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tumors in perioperative setting
    Tumeurs MSI/dMMR en péri-opératoire
    A.3.2Name or abbreviated title of the trial where available
    IMHOTEP
    IMHOTEP
    A.4.1Sponsor's protocol code numberET20-093
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCentre Léon Bérard
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMSD
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Léon Bérard
    B.5.2Functional name of contact pointDRCI
    B.5.3 Address:
    B.5.3.1Street Address28 rue Laennec
    B.5.3.2Town/ cityLYON Cedex 08
    B.5.3.3Post code69373
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0) 478 78 29 67
    B.5.5Fax number+33(0) 478 78 27 15
    B.5.6E-mailellen.blanc@lyon.unicancer.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name keytruda (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namepembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    MSI/dMMR tumors or EBV+ gastric cancer
    Tumeurs MSI/ dMMR ou cancer gastrique EBV+
    E.1.1.1Medical condition in easily understood language
    MSI/dMMR tumors or EBV+ gastric cancer
    Tumeurs MSI/ dMMR ou cancer gastrique EBV+
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of pembrolizumab MK-3475 in perioperative setting in patients with untreated localized non-metastatic MSI/dMMR carcinomas, independently of their anatomical origin.
    Evaluer l’efficacité du pembrolizumab MK-3475 en situation péri-opératoire chez des patients présentant un carcinome MSI/dMMR localisé non métastatique non traité, indépendamment de leur origine anatomique.
    E.2.2Secondary objectives of the trial
    To evaluate:
    • The safety of the perioperative treatment according to NCI CTC-AE v5,
    • The post-operative morbidity according to modified Clavien Dindo scoring,
    • The R0 resection rate,
    • The major pathological response (≤ 10% residual viable tumor) rate
    • The recurrence-free survival (RFS) using RECIST 1.1,
    • The overall response rate (ORR) at 4 weeks after the injection of pre-operative pembrolizumab using RECIST 1.1,
    • The rate of second cancers in the Lynch syndrom spectrum,
    • The overall survival (OS),
    • The progression-free survival (PFS2) after recurrence,
    • The quality of life (QoL),
    • The prognostic value of lung immune prognostic index (LIPI).
    Evaluer :
    • La tolérance du traitement péri-opératoire selon le NCI CTC-AE v5,
    • La morbidité post-opératoire selon la classification de Dindo-Clavien,
    • Le taux de résection R0,
    • Le taux de réponse pathologique majeure (< 10% de tumeur résiduelle viable),
    • Le taux de survie sans récidive (RFS) selon les critères RECIST 1.1,
    • Le taux de réponse globale (ORR) 4 semaines après l’injection du pembrolizumab MK-3475 pré-opératoire selon les critères RECIST 1.1,
    • Le taux de second cancer chez les patients atteints d’un syndrome de Lynch,
    • La survie globale (OS),
    • La survie sans progression (PFS) après récidive,
    • La qualité de vie (QoL),
    • La valeur pronostique de l’index pronostique immun LIPI pulmonaire (Lung Immune Prognostic Index).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The objectives of this ancillary program are triple: to assess molecular and/or immunological biomarkers before and in the course of treatment that can
    (i) predict the response and/or resistance to pembrolizumab,
    (ii) predict tumor relapse after surgery,
    (iii) compare the data according to the primary tumor independently of the MMR status.
    Les objectifs du programme ancillaire sont triples : évaluer les biomarqueurs immunologiques et/ou moléculaires, avant et durant le traitement, qui pourraient :
    (i) prédire la réponse et/ou la résistance au pembrolizumab MK-3475,
    (ii) prédire la rechute après la chirurgie,
    (iii) et comparer ces données selon la tumeur initiale indépendamment du statut MMR.
    E.3Principal 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:
    - Colorectal Cancer (cT3/T4 N0 M0 ou cT N+ M0 on thoraco-abdomino-pelvic TAP CT-scan and echo-endoscopy) OR
    - Oesogastric (gastric, gastro-oesophageal or oesophageal) cancer (cT2 to cT4, N, M0 on TAP CT-scan and echo-endoscopy) OR
    - Endometrial carcinoma (stage III) OR
    - Other tumor types (cT2 to cT4, N, M0 on TAP CT-scan and echo-endoscopy) : biliary tract or pancreas adenocarcinoma, small bowel adenocarcinoma (duodenum, jejunum, ileum), peritoneum adenocarcinoma.
    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 tumI4. 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  50 ml/min using either MDRD or CKD-EPI formula, (MDRD will be used for patients > 65 years)
    - 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.
    ...See the protocol
    I1. Age > 18 ans à la date de signature du consentement éclairé de participation
    I2. Tumeur localisée non métastatique histologiquement prouvée, incluse dans l’une des 4 cohortes :
    - Cancer du côlon (cT3/T4 N0 M0 ou cT N+ M0 sur scanner TAP et écho-endoscopie) OU,
    - Cancer œsogastrique (cT2 à cT4 N M0 sur scanner TAP et écho-endoscopie) (gastrique, gastro-œsophagien ou œsophagien) OU
    - Carcinome de l’endomètre (stade III) OU
    - Autres types de tumeur (cT2 à cT4, N, M0 sur scanner TAP et écho-endoscopie): adénocarcinome du pancréas, des voies biliaires, de l’intestin grêle (duodénum, jéjunum, iléon) ou du péritoine
    I3. Statut MSI/dMMR établi par immunohistochimie (IHC) [expression des protéines MMR] et réaction en chaîne par polymérase (PCR) [les deux techniques sont requises] et validé par le coordonnateur/centre de coordination.
    Les tumeurs MMR et/ou MSI seront évaluées par IHC avec quatre anticorps (anti-MLH1, anti-MSH2, anti-MSH6 et anti-PMS2) et par PCR (le panel pentaplex est recommandé: BAT-25, BAT-26, NR-21, NR-24 et NR-27) avant la sélection du patient. La perte d’expression par analyse IHC des protéines MLH1 et PMS2 / ou MSH2 et MSH6 / ou MSH6 seule / ou PMS2 seule indique le statut dMMR, et une tumeur avec ≥ 2 marqueurs instables parmi 5 marqueurs microsatellites analysés par PCR (BAT25, BAT26, NR21, NR24 et NR27) prouve le statut MSI/dMMR.
    OU cancers gastriques EBV-positifs. La positivité de l'EBV sera évaluée par hybridation in situ (HIS) d’EBER (ARN codé par EBV) (sonde flexible EnVision EBER-PNA (Dako)). L'intensité de la coloration (faible, modérée ou intense) et le pourcentage de cellules positives seront enregistrés. Les cas montrant une coloration nucléaire pour au moins 5% des cellules tumorales seront considérés comme positifs pour l'infection à EBV.
    I4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 à 1, évalué dans les 7 jours précédant l’inclusion.
    I5. Fonctions médullaire, hépatique et rénale adéquates avec :
    - Hémoglobine ≥ 9 g/dl ou ≥ 5.6 mmol/l, Neutrophiles ≥ 1.0 x 109/l, Plaquettes ≥ 100 x 109/l,
    - Créatinine sérique ≤ 1.5 x LNS ou clairance de la créatinine. ≥ 50 ml/min/1.73m² calculée selon la formule MDRD ou CKD-EPI. La MDRD sera utilisée chez les patients > 65 ans.
    - ASAT et ALAT ≤ 3 x LNS, bilirubine totale ≤ 1.5 x LNS (ou bilirubine directe ≤ LNS pour les patients ayant une bilirubine totale > 1.5 × LNS)
    - INR ou TP ≤1.5 × LNS sauf si le patient reçoit un traitement anticoagulant tant que TP ou aPTT (temps de céphaline activée) se situe dans la plage thérapeutique d’utilisation prévue des anticoagulants.
    ...Voir le protocole
    E.4Principal exclusion 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, 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.
    ...See the protocol
    E1. Tumeurs MSS/pMMR.
    E2. Maladie métastatique (stade IV).
    E3. Test HIV positif avec un nombre de CD4 inférieur à 400 cellules/mm3.
    E4. Virus de l'hépatite B actif (HBV), défini par un test positif pour l'antigène de surface de l'hépatite B [HBsAg] avant l'inclusion) ou infection par le virus de l'hépatite C (HCV).
    E5. Maladie auto-immune systémique active qui a nécessité un traitement systémique au cours des 2 dernières années (i.e. avec l'administration d'agents modificateurs de la maladie, corticostéroïdes ou traitement immunosuppresseur). Les traitements substitutifs (par exemple thyroxine, insuline) ne sont pas considérés comme une forme de traitement systémique et sont autorisés.
    ...Voir le protocole
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the rate of complete pathological response (pCR) after surgery.
    A complete pathological response will be defined as 0% viable tumor cells.
    Le critère de jugement principal sera le taux de réponse pathologique complète (pRC) après la chirurgie. Une réponse pathologique complète sera définie par 0% de cellules tumorales viables.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Rate of complete pathological response (pCR) after surgery.
    0% viable tumor cells
    E.5.2Secondary end point(s)
    •Safety profile
    •Rate of surgical complications
    •Percentage of patients with R0 resection
    •Percentage of patients with major pathological response
    •RFS
    ...See the protocol
    E.5.2.1Timepoint(s) of evaluation of this end point
    • 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.
    • Rate of surgical complications (post-operative morbidity) assessed according to modified Clavien Dindo scoring.
    • Percentage of patients with R0 resection.
    • Percentage of patients with major pathological response (≤ 10% residual viable tumor).
    • RFS, defined as the time from the date of first study treatment administration to the date of first documented recurrence (second cancer excluded).
    ...See the protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned25
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLP
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months60
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the physician discretion
    A la discrétion du médecin
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-20
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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