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    Summary
    EudraCT Number:2016-004740-11
    Sponsor's Protocol Code Number:MK-3475-522
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2017-01-23
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2016-004740-11
    A.3Full title of the trial
    A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab plus Chemotherapy vs Placebo plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)
    Estudo de fase III, aleatorizado, em dupla ocultação para avaliar pembrolizumab associado a quimioterapia versus placebo associado a quimioterapia como tratamento neoadjuvante e pembrolizumab versus placebo como tratamento adjuvante para o cancro da mama triplo negativo (CMTN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase III, Randomized, Double-blind Study to Evaluate Chemotherapy plus Pembrolizumab vs Chemotherapy plus Placebo as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)
    Estudo de fase III, aleatorizado, em dupla ocultação para avaliar pembrolizumab associado a quimioterapia versus placebo associado a quimioterapia como tratamento neoadjuvante e pembrolizumab versus placebo como tratamento adjuvante para o cancro da mama triplo negativo (CMTN)
    A.3.2Name or abbreviated title of the trial where available
    Evaluate chemotherapy plus MK-3475 vs chemotherapy plus placebo and MK-3475 vs placebo for TNBC
    Avaliação de quimoterapia com MK-3475 vs. quimioterapia com placebo e MK-3475 vs. placebo para CMTN
    A.4.1Sponsor's protocol code numberMK-3475-522
    A.5.4Other Identifiers
    Name:KeynoteNumber:522
    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, 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 LLC, 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 LLC, a subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointGlobal Clinical Trial Operations
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave., P.O. Box 2000
    B.5.3.2Town/ cityRahway, New Jersey
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1267305 1537
    B.5.6E-mailthao.dang@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
    Neoadjuvant and adjuvant treatment for locally-advanced TNBC
    E.1.1.1Medical condition in easily understood language
    Triple Negative Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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 the rate of pCR using the definition of ypT0/Tis ypN0 (i.e.,
    no invasive residual in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist at the time of definitive surgery in subjects with locally advanced TNBC
    2.To evaluate the event-free survival (EFS) as assessed by Investigator in subjects with locally advanced TNBC during the Neoadjuvant and Adjuvant Treatment Phases.
    E.2.2Secondary objectives of the trial
    1. To evaluate overall survival (OS) in subjects with locally advanced
    TNBC tumors.
    2. To evaluate the rate of pCR using an alternative definition, ypT0 ypN0
    (i.e., no invasive or noninvasive residual in breast or nodes) as assessed
    by the local pathologist at the time of definitive surgery in subjects with
    locally advanced TNBC and in individuals with programmed death ligand
    1 (PD-L1) positive (+) tumors (combined positive score [CPS] ≥1).
    3. To evaluate the rate of pCR using the definition of (ypT0/Tis ypN0)
    (i.e., no invasive residual in breast or nodes; noninvasive breast
    residuals allowed) as assessed by the local pathologist at the time of
    definitive surgery in individuals with PD-L1 (+) tumors (CPS ≥1).
    4. To evaluate the EFS as assessed by Investigator in individuals withPDL1
    (+) tumors (CPS ≥1).
    For a complete list of all secondairy objectives, please refer to the
    protocol.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sub-study FBR
    Title : Future Biomedical Research
    Date and version : 16 dec 16
    Objectives : The specimens consented and/or collected in this trial as outlined in Section 7.1.3.7 – Future Biomedical Research Samples will be used in various experiments to understand:
    -The biology of how drugs/vaccines work
    - Biomarkers responsible for how a drug/vaccine enters and is removed by the body
    - Other pathways drugs/vaccines may interact with
    - The biology of disease
    The specimen(s) may be used for future assay development and/or drug/vaccine development.

    Sub-study PK
    Title : Pharmacokinetic
    Date and version : 16 dec 16
    Objectives : Sample collection, storage and shipment instructions for serum PK and anti -pembrolizumab antibody samples will be provided in the Procedures Manual. These studies will only be performed for the required minimum number of subjects in Japan and non-Japanese subjects who choose to participate. If ongoing anti-drug antibodies (ADAs) and/or PK results continue to be consistent with existing ADA and/or PK data from other pembrolizumab clinical studies, it may be decided to discontinue or reduce further sample collection in this study.

    Sub-study MRI
    Title : Breast Magnetic Resonance Imaging
    Date and version : 16 dec 16
    Objectives : Breast MRIs will be performed in a subset of subjects with locally advanced TNBC who choose to participate. If a subject has consented to participating in the Breast MRI, breast MRIs are performed at screening, after the Neoadjuvant Treatment Phase, Treatment 1 Cycle 4, and after the Neoadjuvant Treatment Phase, Treatment 2 Cycle 4 before definitive surgery (See Protocol Section 7.1.2.9.1 – Breast MRI for more details). Changes from the baseline will be assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Breast MRI images will be sent to a designated central vendor for collection, quality review, and independent imaging review.
    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. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    2.Be a male or female subject >18 years of age on day of signing informed consent.
    3.Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
    4.Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by the investigator based on radiological and/or clinical assessment: T1c, N1-N2, T2, N0-N2, T3, N0-N2,T4a-d, N0-N2
    5.Provide a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory.
    6.Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.
    7.Demonstrate adequate organ function as defined in the protocol. All screening labs should be performed within 10 days of treatment initiation.
    8.Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
    9.Males and female subjects of childbearing potential must be willing to use an adequate method of contraception. Contraception, for the course of the study through 12 months after the last dose of study medication for subjects who have received cyclophosphamide, and 6 months after the last dose of study medication for subjects who did not.
    10.(Female subject of childbearing potential) Have a negative urine or serum p regnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or borderline a serum pregnancy test will be required.
    E.4Principal exclusion criteria
    1.Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
    2. Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
    3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137) or has previously participated in MK-3475 clinical trials.
    4. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 4 weeks of the first dose of treatment in this current trial.
    5.Has received a live vaccine within 30 days of the first dose of study treatment.
    6.Has an 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) is not considered a form of systemic treatment.
    7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy (ie, dosing exceding 10 mg daily of prednisone or equivalent) within 7 days prior to the first dose of trial treatment.
    8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV
    1/2 antibodies).
    9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    11. Has an active infection requiring systemic therapy.
    12.Has significant cardiovascular disease, such as:
    a) History of myocardial infarction, acute coronary syndrome or coronary
    angioplasty/stenting/bypass grafting within the last 6 months
    b) Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV
    13. Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject’s participation for the full duration of the trial.
    14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    15. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the screening visit through 12 months after the last dose of trial treatment for subjects who have received cyclophosphamide, and for 6 months after the last dose of study medication for subjects who have not.
    16. Has a known hypersensitivity to the components of the study therapy or its analogs.
    17. Has a known history of active TB (Bacillus Tuberculosis)
    E.5 End points
    E.5.1Primary end point(s)
    1.Pathological complete response rate (ypT0/Tis ypN0) in subjects with locally advanced TNBC.
    2. Event-free survival (EFS) in subjects with locally advanced TNBC.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After Definitive Surgery and at any point PD/Recurrance occurs
    E.5.2Secondary end point(s)
    Pathological complete response rate (ypT0 ypN0) in subjects with locally advanced TNBC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After Definitive Surgery, any point PD/Recurrance occurs, overall survival (time of death)
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 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 EEA56
    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
    Colombia
    Israel
    Japan
    Korea, Republic of
    Taiwan
    United States
    France
    Poland
    Sweden
    Spain
    Germany
    Italy
    Ireland
    Portugal
    Russian Federation
    Turkey
    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 years8
    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 years8
    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: 1075
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 565
    F.4.2.2In the whole clinical trial 1150
    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)
    After subjects have completed the adjuvant treatment phase, he/she will enter into a long term follow up phase. These Long Term Follow Up visits will be in-office visits with required assessments at protocol-specified timepoints. These timepoints are: years 1-2 visits are every 3 months; years 3-4 visits are every 6 months, and years 5+ are annually. Any scans to assess disease recurrence are performed per local/institutional 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 Decision2017-03-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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