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    Summary
    EudraCT Number:2015-004567-36
    Sponsor's Protocol Code Number:MK-3475-240
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-04-12
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2015-004567-36
    A.3Full title of the trial
    A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-Line Therapy in Subjects with Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-240)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase III Study of Pembrolizumab (MK 3475) plus Best Supportive Care in Subjects with Advanced Hepatocellular Carcinoma
    A.3.2Name or abbreviated title of the trial where available
    Phase III Study of MK 3475 + Best Supportive Care in Subjects with Advanced Hepatocellular Carcinoma
    A.4.1Sponsor's protocol code numberMK-3475-240
    A.5.4Other Identifiers
    Name:KEYNOTENumber:240
    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 organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc.
    B.5.2Functional name of contact pointAbby Siegel
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, P.O. Box 100
    B.5.3.2Town/ cityWhitehouse Station, NJ
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17325942756
    B.5.6E-mailabby.siegel@merck.com
    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 No
    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.3.10 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
    Hepatocellular Carcinoma
    E.1.1.1Medical condition in easily understood language
    Hepatocellular Carcinoma
    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 LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Objective: To compare progression-free survival (PFS) per RECIST 1.1 assessed by a blinded central imaging vendor.
    2. Objective: To compare OS between pembrolizumab plus BSC versus placebo plus BSC.
    E.2.2Secondary objectives of the trial
    1. Objective: To compare objective response rate (ORR) per RECIST 1.1 assessed by a blinded central imaging vendor.
    2. Objective: To evaluate the duration of response (DOR), disease control rate (DCR) and time to progression (TTP), per RECIST 1.1 assessed by a blinded central imaging vendor.
    3. Objective: Evaluate the safety and tolerability profile of pembrolizumab.
    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 and tissue) 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. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research (FBR). However, the subject may participate in the main trial without participating in FBR.
    2. Be 18 years of age on day of signing informed consent.
    3. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible). Radiologic confirmation diagnosis is provided by the study site. Definition of radiological confirmation: Clinical findings consistent with the diagnosis of liver cirrhosis and a liver mass measuring at least 2 cm with characteristic vascularization (intense enhancement seen in the hepatic arterial-dominant phase and contrast washout in the late portal venous phase) seen in either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI).
    4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach (see Section 12.8).
    5. Have a Child-Pugh class A liver score within 7 days of first dose of study drug.
    6. Have a predicted life expectancy of >3 months.
    7. Have at least one measurable lesion based on RECIST 1.1 as confirmed by the blinded central imaging vendor.
    8. Have a performance status of 0 or 1 using the ECOG Performance Scale within 7 days of first dose of study drug.
    9. Have documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib. Sorafenib intolerance definition: Any Grade ≥2 drug-related AE which 1) despite supportive therapy, recurred after sorafenib treatment interruption of at least 7 days and dose reduction resulting in the subject requesting, or the physician recommending discontinuation due to toxicity. OR 2) required discontinuation of sorafenib due to toxicity, recommended by the physician with no rechallenge.
    10. Subjects with chronic infection by HCV who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, subjects with successful HCV treatment are allowed as long as there are ≥4 weeks between achieving sustained viral response (SVR12) and start of study drug. Successful HCV treatment definition: SVR12.
    11. Has been treated with anti-Hepatitis B therapy. Controlled (treated) hepatitis B subjects will be allowed if they meet the following criteria: Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout study treatment. Subjects who are anti-HBc (+), negative for HBsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis.
    12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication (Cycle 1, Day 1). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    13. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception for the course of the study, starting with the first dose of study medication through at least 120 days or longer based on local regulation after the last dose of study medication.
    14. Male subject of childbearing potential (Section 5.7.2) must agree to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose of study medication (Cycle 1, Day 1) through 120 days after the last dose of study medication.
    15. Demonstrate adequate organ function
    E.4Principal exclusion criteria
    1. Is currently participating, or has participated, in a study of an investigational agent and received study therapy, herbal/complementary oral or IV medicine, or used an investigation device within 4 weeks of the first dose of treatment. Subjects must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from AEs due to any prior therapy.
    2. Has received sorafenib within 14 days of first dose of study medication.
    3. Has had esophageal or gastric variceal bleeding within the last 6 months. All subjects will be screened for esophageal varices, unless such screening has been performed in the past 12 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting study treatment.
    4. Has clinically apparent ascites on physical examination.
    5. Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.
    6. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Subjects on rifaximin or lactulose to control their hepatic encephalopathy are not allowed.
    7. Had a solid organ or hematologic transplant.
    8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib, prior to start study drug.
    9. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients. (Refer to the respective Investigator’s Brochure for a list of excipients.)
    10. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor
    12. Has received locoregional therapy to liver ranscatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug. Subject is not eligible if aforementioned treatments were administered between last dose of sorafenib and first dose of study medication.
    13. Has had major surgery to liver or other site within 4 weeks prior to the first dose of study drug.
    14. Has had a minor surgery (i.e., simple excision, tooth extraction) ≤7 days prior to the first dose of study treatment (Cycle 1, Day 1).
    15. Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to starting therapy.
    16. Has a diagnosed additional malignancy within 3 years prior to first dose of study with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers.
    17. Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator.
    18. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    19. Has an active infection requiring systemic therapy.
    20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis.
    21. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
    22. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the first dose of study medication through 120 days or longer based on local regulation after the last dose of trial treatment.
    23. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 agents, or if the subject has previously participated in Merck pembrolizumab clinical trials. 24. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
    25. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
    26. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1).
    E.5 End points
    E.5.1Primary end point(s)
    PFS per RECIST 1.1 criteria as assessed by the blinded central imaging vendor and OS will be used as the primary endpoints.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two Interim analysis to be performed:
    IA1: expected approximately at month 22 at which time 183 OS events are expected to have been accumulated
    IA2: when approximately 232 OS events have been observed (expected at month 28 after study start)

    Final efficacy analysis for OS (assuming not declared futile at the interim analysis); to be performed when at least 273 OS events have been observed, estimated to be 35 months after study start. Results will be reviewed by an external data monitoring committee.
    E.5.2Secondary end point(s)
    1. Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor.
    2. Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central imaging vendor.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. ORR data locked at the time of the IA1, when approximately 183 OS events are observed, will be analyzed at IA1 if Type I error is available for the ORR analysis at this time point according to the multiplicity strategy; otherwise, these data will be analyzed at IA2 or FA, whenever the Type I error is available
    2. Analyses of the DCR, TTP and DOR data will be performed at the time of the interim and final analysis of OS.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 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 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 No
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Belgium
    Canada
    Chile
    Colombia
    Denmark
    France
    Germany
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Norway
    Philippines
    Poland
    Puerto Rico
    Russian Federation
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    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 years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 258
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 408
    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)
    Patient care after the study will be managed by the patient’s primary physician.
    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 Decision2016-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-05
    P. End of Trial
    P.End of Trial StatusOngoing
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