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    The EU Clinical Trials Register currently displays   43800   clinical trials with a EudraCT protocol, of which   7272   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:2016-004351-75
    Sponsor's Protocol Code Number:3475-564
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2017-04-03
    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 ConcernedGermany - PEI
    A.2EudraCT number2016-004351-75
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ph 3 Placebo-Controlled Trial of Adjuvant MK-3475 in RCC Post Nephrectomy
    A.3.2Name or abbreviated title of the trial where available
    Ph 3 Placebo-Controlled Trial of Adjuvant MK-3475 in RCC Post Nephrectomy
    A.4.1Sponsor's protocol code number3475-564
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03142334
    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 LLC
    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 LLC
    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 LLC
    B.5.2Functional name of contact pointGCTO
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave., P.O. Box 2000
    B.5.3.2Town/ cityRahway, NJ
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17325941586
    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.3.9.4EV 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
    Treatment of participants with RCC in the adjuvant setting
    E.1.1.1Medical condition in easily understood language
    Renal Cell Carcinoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10038395
    E.1.2Term Renal carcinoma
    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
    To compare disease-free survival (DFS) as assessed by the investigator for participants treated with pembrolizumab versus those receiving placebo
    E.2.2Secondary objectives of the trial
    1. To compare
    a. overall survival (OS) for participants treated with pembrolizumab vs those receiving placebo
    b. the safety and tolerability profiles for participants treated with pembrolizumab vs those receiving placebo
    c. measures of disease recurrence-specific survival (DRSS), as assessed by the investigator, in participants treated with pembrolizumab vs those receiving placebo
    d. event-free survival (EFS) as assessed by the blinded Independent radiology review for participants treated with pembrolizumab vs those receiving placebo
    e. DFS and OS according to participants' PD-L1 expression Status (Positive, Negative) for participants treated with pembrolizumab vs those receiving placebo
    2. To evaluate patient-reported outcomes (PROs) with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ- C30) and the Functional Assessment of Cancer Therapy Kidney Symptom Index – Disease Related Symptoms (FKSI-DRS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Must have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features. Diagnosis of RCC with clear cell component is to be made by the investigator and does not require central histology review.
    2.Be ≥ 18 years of age on day of signing informed consent.
    3.Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    4.Female participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug must be collected within 10 days prior to randomization.
    5.Male participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug.
    6.The participant provides written informed consent/assent for the trial. The participant may also provide consent/assent for Future Biomedical Research; however the participant may participate in the main trial without participating in Future Biomedical Research.
    7.Have intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:
    a)Intermediate-high risk RCC
    -pT2, Gr. 4 or sarcomatoid, N0, M0
    -pT3, Any Gr., N0, M0
    b)High risk RCC
    - pT4, Any Gr. N0, M0
    -pT Any stage, Any Gr., N+, M0
    c)M1 NED RCC -participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following:
    - the time of nephrectomy (synchronous) or,
    - ≤1 year from nephrectomy (metachronous)
    8.Have received no prior systemic therapy for advanced RCC
    9.Have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins.
    10.Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization.
    11.Must be tumor-free as assessed by the Investigator and validated by either CT or MRI scan of the brain and CAP and a bone scan ≤28 days from randomization. All baseline scans must be sent to the central imaging vendor and receipt must be confirmed prior to randomization .
    12.Must have provided adequate tissue per the following:
    - Nephrectomy only: tissue from nephrectomy (required).
    - Synchronous M1 NED: tissue from nephrectomy (required) AND, metastasectomy issue (if available).
    - Metachronous M1 NED: tissue from metastasectomy (required) AND, nephrectomy tissue (if available).
    Adequacy of the samples for biomarker analysis will be evaluated by a central laboratory.
    13.Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
    14.Have adequate organ function as defined in the protocol. Specimens.
    E.4Principal exclusion criteria
    1.Has had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED participants, within 12 weeks prior to randomization.
    2.Has received prior radiotherapy for RCC.
    3. Has pre-existing brain or bone metastatic lesions.
    4.Has residual thrombus post nephrectomy in the vena renalis or vena cava
    5.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 the first dose of study treatment.
    6.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). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
    treatment and is allowed.
    7.Has a known additional malignancy that is progressing or required active treatment ≤3 years ago. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that has
    undergone potentially curative therapy.
    8.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    9.Has an active infection requiring systemic therapy
    10. Has a history of, or is currently on, dialysis
    11.Has a known history of human immunodeficiency virus infection. No human immunodeficiency virus testing is required unless mandated by local health authority.
    12.Has a known active hepatitis B (hepatitis B surface antigen reactive) or hepatitis C virus (eg, hepatitis C virus [HCV] RNA [qualitative] is detected)
    13.Has a known history of active tuberculosis (Bacillus tuberculosis).
    14.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
    15.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial in the opinion of the investigator 16.Has had a prior solid organ transplant.
    17.Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    18.A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours before randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Participants must be excluded/discontinued from the trial in the event of a positive or borderline positive test result.
    19.Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 120 days after the last dose of study treatment.
    20.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, CD137) or has previously participated in a Merck pembrolizumab (MK 3475) clinical trial.
    21.Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before first dose of study treatment or not recovered (ie, must be ≤Grade 1 or at baseline) from AEs due to previously administered agents.
    22.Has received a live vaccine within 30 days prior to the first dose of study treatment. 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, 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
    23.Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    Disease-free survival (DFS) as assessed by the investigator
    E.5.1.1Timepoint(s) of evaluation of this end point
    • First Interim Analysis (IA1)
    Interim analysis for DFS
    Timing: When at least 265 disease recurrence events by Investigator assessment have accrued and a minimum follow-up (time from last
    participant randomized to IA1) of 12 months is achieved.
    • Second Interim Analysis (IA2)
    Final analysis for DFS
    Timing: Final analysis of DFS when approximately 332 DFS events by investigator assessment have accrued if DFS is not rejected at IA1.
    E.5.2Secondary end point(s)
    Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • First Interim Analysis (IA1)
    Interim analysis for OS.
    Timing: When at least 265 disease recurrence events by Investigator assessment have accrued and a minimum follow-up (time from last
    participant randomized to IA1) of 12 months is achieved. Approximately 94 OS events are expected at this time.
    • Second Interim Analysis (IA2)
    Interim analysis for OS
    Timing: when approximately 332 DFS events by investigator assessment have accrued if DFS is not rejected at IA1. Approximately 132 OS events
    are expected at this time.
    • Third Interim Analysis (IA3)
    Interim analysis for OS
    Timing: When approximately 172 OS events have accrued.
    • Final analysis (FA)
    Final analysis for OS
    Timing: When approximately 200 OS events have accrued.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA74
    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
    Chile
    China
    Colombia
    Japan
    Korea, Republic of
    New Zealand
    Taiwan
    United States
    Finland
    France
    Poland
    Spain
    Czechia
    Germany
    Italy
    Ireland
    Russian Federation
    United Kingdom
    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 years6
    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 years6
    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: 475
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 475
    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 state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 456
    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 as this is an adjuvant study; if/when subject has disease recurrence, the subject will be withdrawn from the study in order to receive standard of care therapy
    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 Decision2017-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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