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    Summary
    EudraCT Number:2014-004026-17
    Sponsor's Protocol Code Number:MK-3475-057
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-02-29
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-004026-17
    A.3Full title of the trial
    A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects with High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab (MK-3475) in High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Patients Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy
    A.3.2Name or abbreviated title of the trial where available
    Pembrolizumab (MK-3475) in high risk NMIBC patients unresponsive to BCG
    A.4.1Sponsor's protocol code numberMK-3475-057
    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 pointElizabeth Hopkins
    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 code8889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919599 7734
    B.5.6E-mailelizabeth.hopkins@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 nameMK-3475
    D.3.9.4EV Substance CodeSUB91641
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-Muscle Invasive Bladder Cancer (NMIBC)
    E.1.1.1Medical condition in easily understood language
    Bladder Cancer
    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 PT
    E.1.2Classification code 10005003
    E.1.2Term Bladder cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In:
    Cohort A - Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
    And
    Cohort B - Subjects without CIS at baseline (High Grade Ta or Any Grade T1)

    To evaluate anti-tumor activity of pembrolizumab (MK-3475) by evaluating the absence of high risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review.
    E.2.2Secondary objectives of the trial
    To evaluate anti-tumor activity of MK-3475:
    Cohort A -CIS at baseline
    1. by CR rate of any disease
    2. by DOR of high risk NMIBC and any disease (responders only)
    3. in PD-L1+ subjects by CR rate of high risk NMIBC and any disease
    4. in PD-L1+ subjects by DOR of high risk NMIBC and any disease (responders only)
    5. in the study population and in PD-L1+ subjects by:
    a. DOR rate at specific time points of both high risk NMIBC and any disease (responders only)
    b. PFS, to worsening of grade or stage or death
    c. PFS, to muscle invasive or metastatic disease or death
    d. OS

    Cohort B -no CIS at baseline
    1. by DFS rate of any disease
    2. in PD-L1 + subjects by 12-month DFS rate of high risk NMIBC and any disease
    3. in the study population and in PD-L1+ subjects by:
    a. Overall DFS and 3-month/6-month DFS rates of high risk NMIBC and any disease
    b. PFS, to worsening of grade or stage or death
    c. PFS, to muscle invasive or metastatic disease or death
    d. OS
    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) 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. Have a histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, High Grade Ta and/or CIS) transitional cell carcinoma of the bladder.
    2. In subjects who have papillary tumors (Ta and T1), a complete TURBT must have been performed, as characterized by: attainment of a visually complete resection of all papillary tumors (Ta and T1). Residual CIS not amenable to complete transurethral resection is acceptable. The most recent cystoscopy/TURBT must have been performed within 12 weeks of first dose of trial treatment.
    3. Have been treated with adequate BCG therapy and have developed high risk NMIBC that is unresponsive to BCG therapy.
    4. Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating surgeon.
    5. Have provided tissue for biomarker analysis from the most recent cystoscopy/TURBT procedures from which tumor sample is available.
    6. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG)
    Performance Scale. (Max of 5% ECOG of 2.)
    7. Demonstrate adequate organ function.
    8. 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 and be willing to use contraception in accordance with the Protocol.
    E.4Principal exclusion criteria
    1. Has muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma.
    2. Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium.
    3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
    4. Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of the most recent cystoscopy/TURBT to starting trial treatment.
    5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
    6. Has a known additional malignancy that is progressing or requires active treatment.
    7. Has an active autoimmune disease that has required systemic treatment in past 2 years.
    8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the planned first dose of the study. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor.
    9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    10. Has an active infection requiring systemic therapy, including active or intractable urinary tract infection (UTI) in the last month.
    11. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
    12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
    13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
    14. Has known active Hepatitis B or Hepatitis C.
    15. Has received a live virus vaccine within 30 days of planned start of trial treatment.
    16. Has had an allogenic tissue/solid organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    Cohort A: CR rate of high risk NMIBC in the overall population.

    Cohort B: 12-month DFS rate of high risk NMIBC in the overall population.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
    Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
    Final Analysis = Full Enrollment plus 9 months
    E.5.2Secondary end point(s)
    Cohort A: CR rate of any disease in the overall population; DOR of high risk NMIBC and any disease.

    Cohort B: 12-month DFS rate of any disease in the overall population.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
    Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
    Final Analysis = Full Enrollment plus 9 months
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Finland
    France
    Greece
    Ireland
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Russian Federation
    Sweden
    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 years3
    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 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: 86
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 174
    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 50
    F.4.2.2In the whole clinical trial 260
    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)
    Subjects who complete study treatment will continue into the post treatment tumor assessment period for an additional 3 years for a total of 5 years. Subjects who don't complete treatments and discontinue, depending on reason, will continue to have post treatment tumor assessments for follow up of disease status for a total duration of 5 years, or will enter survival follow-up. All participants will be followed for overall survival until death, withdrawal of consent, or the end of the study.
    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 Decision2016-02-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-11
    P. End of Trial
    P.End of Trial StatusOngoing
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