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    The EU Clinical Trials Register currently displays   42517   clinical trials with a EudraCT protocol, of which   7000   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2012-004907-10
    Sponsor's Protocol Code Number:MK-3475-006
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-01-18
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2012-004907-10
    A.3Full title of the trial
    A Multi-Center, Randomized, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Patients with Advanced Melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MK-3475 Compared to Ipilimumab in Patients with Advanced Melanoma
    A.4.1Sponsor's protocol code numberMK-3475-006
    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. (hereafter referred to as the SPONSOR or Merck)
    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
    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 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 nameMK3475; SCH900475
    D.3.2Product code PRD742198
    D.3.4Pharmaceutical form Powder for injection
    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 CodeSUB91641
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Myers-Squib
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 nameYervoy
    D.3.4Pharmaceutical form Concentrate for 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 INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Patients with advanced Melanoma
    E.1.1.1Medical condition in easily understood language
    melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10053571
    E.1.2Term Melanoma
    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. To evaluate progression-free-survival (PFS) in patients with advanced MEL receiving either Pembrolizumab or IPI.
    2. To evaluate overall survival (OS) in patients with advanced MEL receiving either Pembrolizumab or IPI.
    E.2.2Secondary objectives of the trial
    1. To evaluate safety, tolerability and adverse experience profile of Pembrolizumab versus IPI.
    2. To evaluate the overall response rate (ORR) in patients with advanced MEL receiving either Pembrolizumab or IPI.
    3. To evaluate OS, PFS and ORR in a subgroup of patients with high PD-L1 expression level receiving either Pembrolizumab or IPI.
    4. To further characterize the pharmacokinetics 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 overeaching goal is to use such information to develop safer, more effective drugs, and/or ensure that subjects receive the correct dose of the correct drug at the correct time.
    E.3Principal inclusion criteria
    1) Patient must have a histologically confirmed diagnosis of unresectable stage III or metastatic MEL not amenable to local therapy.
    Patient may not have a diagnosis of uveal or ocular melanoma.
    Patients who have not received prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for MEL (first line) or who have received prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for MEL (second line) are both eligible. However, the enrollment of either first line or second line patients will be limited to approximately 387 patients. After this limit is reached for either of the group, only patients from the other group will be enrolled.
    Patients must have testing for BRAF mutation prior to study entry. Patients with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy as first-line systemic therapy and be eligible for this study as second line treatment. At the discretion of the investigator, patients with BRAF V600E mutant melanoma who have NOT received a BRAF inhibitor are also eligible for this study as first line treatment if they meet the following additional criteria:
    -LDH<local ULN
    -No clinically significant tumour related symptoms in the judgement of the investigator
    -Absence of rapidly progressing metastatic melanoma in the judgement of the investigator

    2) Patient is male or female and ≥18 years of age on day of signing informed consent.

    3) Patient must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Appendix 6.4).

    4) Patient must have adequate organ function as indicated by the following laboratory values.
    System Laboratory Value
    Hematological:
    Absolute neutrophil count (ANC) ≥1,500 /mcL
    Platelets ≥100,000 / mcL
    Hemoglobin ≥9 g/dL or ≥5.6 mmol/L–
    Renal
    Serum creatinine ≤1.5 X upper limit of normal (ULN)
    Hepatic
    Serum total bilirubin ≤ 1.5 X ULN OR
    Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN
    AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR
    ≤ 5 X ULN for patients with liver metastases
    Coagulation
    International Normalized Ratio (INR) or Prothrombin Time (PT)
    Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy
    as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    ≤1.5 X ULN unless patient is receiving anticoagulant therapy
    as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    5) Patient has a tumour sample (archival or newly obtained biopsy) that is adequate for PD-L1 assessment prior to randomisation. Patients must submit the tumour sample during screening for PD-L1 expression testing at a central pathology laboratory. Patients will be eligible to participate regardless of the level of PD-L1 expression, but will be stratified by PD-L1 expression level (high or low PD-L1 expression level) at the time of randomisation. Patient who do not submit a sample adequate for PD-L1 determination will not be randomised. Patients with an inadequate archival sample may obtain a new biopsy and patients with an inadequate newly obtained biopsy may undergo re biopsy at the discretion of the investigator.

    6) Female patient of childbearing potential has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.

    7) Female patients enrolled in the study, who are not free from menses for >18 months, post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with Visit 1 through 120 days after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives. Spermicides alone are not an acceptable method of contraception.
    Male patients must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study therapy.

    8) The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research

    9) Patient has at least one measurable lesion per RECIST criteria on imaging studies (CT or MRI).
    E.4Principal exclusion criteria
    1) Patient had prior treatment with IPI or other anti-CTLA-4 agent, any anti-PD-1, anti-PD-L1, or anti- PD-L2 agent.

    2) Patient who has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than four weeks earlier.

    3) Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug.

    4) Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.

    5) Patient is on any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication.

    6) Patient has a history of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration. This should exclude adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals can be considered after discussion with Sponsor.

    7) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids for at least two weeks.

    8) Patient previously had a severe hypersensitivity reaction to treatment with another mAb.

    9) Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.

    10) Patient has an active infection requiring systemic therapy.

    11) Patient has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

    12) Patient has a known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected).

    13) Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.

    14) Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

    15) Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).

    16) Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.

    17)Patient has received a live vaccine within 30 days prior to first dose.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint for the trial has been reached.
    The primary efficacy endpoints were progression-free-survival (PFS) (i.e., time from randomization to documented progressive disease or death due to any cause, whichever occurs first) and overall survival (OS) (i.e., the time from randomization to death due to any cause).
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS: Interim analysis 1 and 2
    OS: Interim analysis 1, 2 and final analysis
    E.5.2Secondary end point(s)
    Overall response rate (ORR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Interim analysis 1
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    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
    Australia
    Austria
    Belgium
    Canada
    Chile
    Colombia
    France
    Germany
    Israel
    Mexico
    Netherlands
    New Zealand
    Norway
    Spain
    Sweden
    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
    LPLV
    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 months27
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months27
    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: 480
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 165
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 415
    F.4.2.2In the whole clinical trial 645
    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 Decision2013-02-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-06-03
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