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    Summary
    EudraCT Number:2018-000669-35
    Sponsor's Protocol Code Number:MK-3475-716
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2018-07-02
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-000669-35
    A.3Full title of the trial
    Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-risk Stage II Melanoma
    A.4.1Sponsor's protocol code numberMK-3475-716
    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 pointSama Ahsan
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Avenue, P.O. Box 2000
    B.5.3.2Town/ cityRahway, NJ
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12673055875
    B.5.6E-mailsama.ahsan@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 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 milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    High-risk Stage II melanoma
    E.1.1.1Medical condition in easily understood language
    High Risk Stage II Melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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
    To compare Recurrence-free Survival (RFS) between treatment arms
    E.2.2Secondary objectives of the trial
    1) To compare Distant Metastases-free Survival (DMFS) between treatment arms
    2) To compare Overall Survival (OS) between treatment arms
    3) To assess the safety and tolerability of pembrolizumab compared to placebo in the proportion of adverse events (AEs)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male/female participants who are ≥12 years of age on the day of providing documented informed consent/assent [unless local regulations and/or institutional policies do not allow for participants <18 years of age to participate; for those sites, the eligible population is ≥18 years of age] with surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per AJCC 8th edition guidelines.
    2. Participants must not have been previously treated for melanoma beyond complete surgical resection.
    3. No more than 12 weeks may elapse between final surgical resection and randomization. Treatment should start only after complete wound healing from the surgery. If there is a delay of 1 to 7 days exceeding 12 weeks due to unforeseen circumstances, the eligibility should be discussed with the Sponsor and the decision documented. A delay of 1 to 7 days for screening imaging requirements will be allowed if sponsor has allowed 1 week extension between surgical resection and randomization.
    4. Have no evidence of metastatic disease on imaging as determined by investigator assessment. All suspicious lesions amenable to biopsy should be confirmed negative for malignancy
    5. Have a performance status of 0 or 1 on the ECOG Performance Scale at the time of enrollment, LPS score ≥50 (for participants ≤16 years old.), or a KPS score ≥50 (for participants >16 and <18 years old)
    6. Participant must have recovered adequately from toxicity and/or complications from surgery prior to starting study treatment
    7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    a.) Is not a woman of childbearing potential (WOCBP)
    OR
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year) or be abstinent from heterosexual
    intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) as described in Appendix 3 during the
    intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the
    potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 72 hours before the
    first dose of study intervention.
    • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the
    participant must be excluded from participation if the serum pregnancy result is positive.
    • Abstains from breastfeeding during the study treatment period and for at least 120 days after study treatment.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those
    participating in clinical studies.
    8. The participant (or legally acceptable representative if applicable) provides documented informed consent/assent for the study and agrees to distant metastasis-free survival (DMFS) and Overall Survival (OS) data collection until these study endpoints are reached
    9. The participant provides consent/assent for future biomedical research. However, the participant may take part in the main study without participating in future biomedical research
    10. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment
    E.4Principal exclusion criteria
    1. Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years
    2. 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 drug
    3. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
    4. A WOCBP who has a positive urine 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
    5. 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)
    6. Has received prior systemic anticancer therapy for melanoma including investigational agents
    7. Has received a live vaccine within 30 days prior to the first dose of study drug. Note: administration of killed vaccines is allowed.
    8. 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 the first dose of study treatment
    9. Has severe hypersensitivity (≥Grade 3) to any pembrolizumab excipients
    10. 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
    11. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    12. Has an active infection requiring systemic therapy
    13. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as Hepatitis C virus RNA [qualitative] is detected) infection. No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
    15. Has a history of active tuberculosis (Bacillus tuberculosis)
    16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
    17. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    18. Has had an allogeneic tissue/solid organ transplant
    E.5 End points
    E.5.1Primary end point(s)
    Recurrence-free survival (RFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    RFS: time from randomization to (1) any recurrence (local or regional [including invasive ipsilateral tumor and invasive loco regional tumor], or distant) as assessed by the investigator, or (2) death due to any cause (both cancer and non-cancer causes of death)
    E.5.2Secondary end point(s)
    1. Distant Metastasis-free Survival (DMFS)
    2. Overall Survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • OS: The time from randomization to death due to any cause.
    • DMFS: The time from randomization to appearance of a distant metastasis as assessed by the investigator. A distant metastasis refers to cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes
    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 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 No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life Patient Reported outcomes
    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 Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part 2 - Unblinded, Crossover/Rechallenge
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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
    Brazil
    Canada
    Chile
    Israel
    New Zealand
    United States
    France
    Poland
    Spain
    Switzerland
    Germany
    Italy
    Belgium
    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 years14
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years15
    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 Yes
    F.1.1Number of subjects for this age range: 2
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 810
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 142
    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 state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 515
    F.4.2.2In the whole clinical trial 954
    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)
    Standard of Care
    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 Decision2018-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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