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    The EU Clinical Trials Register currently displays   43839   clinical trials with a EudraCT protocol, of which   7280   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2018-004800-20
    Sponsor's Protocol Code Number:MK-3475-937
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-03-06
    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 ConcernedSweden - MPA
    A.2EudraCT number2018-004800-20
    A.3Full title of the trial
    A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) versus Placebo as Adjuvant Therapy in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablation (KEYNOTE-937)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Adjuvant Therapy with Pembrolizumab Versus Placebo in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablation
    A.4.1Sponsor's protocol code numberMK-3475-937
    A.5.4Other Identifiers
    Name:INDNumber:123 482
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.3.4Pharmaceutical 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.3.9.4EV 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adjuvant treatment of HCC
    E.1.1.1Medical condition in easily understood language
    This is a study in early HCC (liver cancer) to evaluate the safety and efficacy of pembrolizumab as adjuvant therapy
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare Recurrence-Free Survival (RFS)
    2. To compare Overall Survival (OS)
    E.2.2Secondary objectives of the trial
    1. To evaluate the safety and tolerability
    2. To compare score change from baseline in global quality of life (QoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/QoL scale and EORTC QLQ-HCC18
    3. To characterize health utilities using the EuroQoL-5 Dimension Questionnaire, 5-Level (EQ-5D-5L) health utility scores
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (Blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    E.3Principal inclusion criteria
    1. Has a diagnosis of HCC documented radiologically by AASLD criteria (participants undergoing ablation without a prior biopsy) and/or pathologically (participants undergoing ablation and not meeting AASLD criteria, and participants undergoing surgical resection); fibrolamellar, sarcomatoid and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible and:
    A. Has a complete radiological response after surgical resection (R0 resection) and an intermediate risk (Stage IB), high risk (Stage II, IIIA) or very high risk of recurrence (subtypes of Stage IIIB as described below) as per American Joint Committee on Cancer (AJCC) 8th edition with adaptations based on tumor characteristics as established by the pathology report
    - Intermediate risk of recurrence: solitary tumor ≥2 cm without microvascular invasion and not histologic grade 3 or 4
    - High risk of recurrence: solitary tumor ≥2 and <10 cm with microvascular invasion or same size and histologic grade 3 or 4, or multiple tumors, none >10 cm, regardless of microvascular invasion or histologic grade
    - Very high risk of recurrence: single tumor or multiple tumors of any size with macrovascular invasion. Stage IIIB tumor(s) with direct invasion of adjacent organs or with perforation of visceral peritoneum will not be eligible
    OR
    B. Has a complete radiological response after local ablation (only radiofrequency or microwave ablation are allowed) and intermediate, high risk of recurrence or very high-risk group
    - Intermediate risk of recurrence: Solitary tumor ≥2 cm and ≤3 cm
    - High risk of recurrence: 2-4 tumors, with all ≤3 cm or one solitary tumor >3 cm and ≤5 cm.
    - Very high-risk group: 2-4 tumors with at least one >3 cm and all ≤5 cm.
    2. No more than 12 weeks must have elapsed between the date of the staging and the date of surgical resection or local ablation.
    3. Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response ≥4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation
    4. Has no radiologic evidence of disease prior to enrollment as per investigator assessment
    5. Has an ECOG performance status of 0 or 1 within 7 days prior to C1D1
    6. Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to C1D1
    7. Has AFP concentration lower than 400 ng/mL within 28 days prior to C1D1 (if there are several AFP values available within 28 days prior to C1D1, the closest AFP value to C1D1 should be below 400 ng/mL)
    8. Has AFP concentration at initial diagnosis prior to resection or ablation available
    9. Participant may have a past or ongoing HCV infection. Participants must have completed their treatment at least 1 month prior to C1D1 or have received at least 1 month of DAA HCV therapy with no DAA-related safety events and stable LFTs. For participants not on anti HCV therapy at the time of randomization, DAAs for treatment of HCV infection can be initiated per Investigator’s discretion, if LFTs are stable after 3-6 months of study intervention upon sponsor consultation.
    10. Participant may have controlled hepatitis B, as long as they meet the following criteria:
    - Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 500 IU/mL should stay on the same therapy throughout study intervention
    - However, participants who are anti-HBc (+), negative for HbsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 500 IU/mL, do not require HBV anti-viral prophylaxis
    11. Has recovered adequately from toxicity and/or complications from the local intervention (surgical resection or local ablation) prior to starting study intervention
    12. Is male or female, at least 18 years of age at the time of signing the informed consent
    13. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    14. Participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the study and agrees to RFS, DMFS, TTR and OS data collection until the study endpoints are reached. The participant may also provide consent/assent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research
    15. All participants who undergo surgical resection will be required to submit a tumor tissue sample during Screening. Participants who undergo local ablation are encouraged to submit a tumor tissue sample during Screening if available. All participants are encouraged to submit surrounding non-tumor tissue during Screening if available
    16. Has adequate organ function
    E.4Principal exclusion criteria
    1. Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years
    2. Has had esophageal or gastric variceal bleeding within the last 6 months. All cirrhotic participants will be screened for esophageal varices with an upper endoscopy, unless such assessment has been performed in the past 12 months before C1D1. If varices are present, they should be treated according to institutional standards before starting study intervention
    3. Has clinically apparent ascites on physical examination
    4. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their hepatic encephalopathy regardless of when the diagnosis of hepatic encephalopathy occurred are not eligible
    5. Has received local therapy to liver ablation other than with radiofrequency or microwave ablation (ie alcohol ablation, transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], local radiation/Stereotactic Body Radiation Therapy [SBRT] or radioembolization)
    6. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
    7. Has an active infection requiring systemic therapy
    8. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry
    9. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    10. Has known active tuberculosis (TB; Bacillus tuberculosis)
    11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
    12. Has received prior systemic anti-cancer therapy for HCC including investigational agents
    13. Is receiving any of the following prohibited concomitant therapies:
    - Antineoplastic systemic chemotherapy or biological therapy
    - Immunotherapy not specified in this protocol
    - Investigational agents other than pembrolizumab
    - Received prior radiotherapy within 2 weeks of start of study intervention
    - Oncological surgical therapy
    - Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. Inhaled or topical steroids are allowed, and systemic steroids at doses ≤10 mg/day prednisone or equivalent are allowed. Exception: steroids may be used for premedication prior to imaging
    14. Has received a live vaccine within 30 days prior to the first dose of study intervention. 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®, [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed
    15. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to C1D1
    16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to C1D1
    17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
    18. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
    19. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstances that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
    20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    21. Has had an allogenic tissue/solid organ transplant
    E.5 End points
    E.5.1Primary end point(s)
    1.Recurrence-Free Survival (RFS)
    2.Overall Survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.Up to ~4 years
    2.Up to ~6 years
    E.5.2Secondary end point(s)
    1.Percentage of participants who experience an adverse event (AE)
    2.Percentage of participants who discontinue study treatment due to an AE
    3.Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Overall Scores and Subscale Scores
    4.Change from Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Scale Score
    5.Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Up to ~6 years
    2.Up to ~1 year
    3.Baseline, time of last patient reported outcome (PRO) assessment (up to ~7 years)
    4.Baseline, time of last PRO assessment (up to ~7 years)
    5.Baseline, time of last PRO assessment (up to ~7 years)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    China
    Colombia
    Hong Kong
    Israel
    Japan
    Korea, Republic of
    Malaysia
    New Zealand
    Peru
    Russian Federation
    Taiwan
    Thailand
    Turkey
    Ukraine
    United States
    Belgium
    Czechia
    Denmark
    France
    Germany
    Hungary
    Ireland
    Italy
    Norway
    Poland
    Portugal
    Sweden
    United Kingdom
    Bulgaria
    Netherlands
    Spain
    Switzerland
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 Yes
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 950
    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)
    None
    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 Decision2019-03-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-08
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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