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    Summary
    EudraCT Number:2014-004026-17
    Sponsor's Protocol Code Number:MK-3475-057
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2015-11-27
    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 ConcernedSweden - MPA
    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) and Pembrolizumab in Combination with Other Investigational Agents 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) and Pembrolizumab in combination with other agents 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 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 pointGlobal Clinical Trials Operations
    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+17325946767
    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.3.1Product 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)
    And
    Cohort C - Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)

    The study is considered to have met its primary objective if the primary
    hypothesis for either Cohort A or Cohort B is successful.

    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.

    To evaluate anti-tumor activity of MK-7684A and MK-4280 by 12-month complete response (CR) rate of high-risk NMIBC, as determined by
    cystoscopy, cytology, biopsy and radiologic imaging by central pathology and radiology review.
    E.2.2Secondary objectives of the trial
    Evaluate anti-tumor activity of MK-3475:
    Cohort A -CIS at baseline
    - CR rate of any disease
    - DOR of high risk NMIBC and any disease (resp only)
    - in PD-L1+ subjects by CR rate of high risk NMIBC and any disease
    - in PD-L1+ subjects by DOR of high risk NMIBC and any disease (resp only)
    - 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 (resp only)

    Cohort B -no CIS at baseline
    - DFS rate of any disease
    - in PD-L1 + subjects by 12-month DFS rate of high risk NMIBC and any disease
    - 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

    Cohort C - CIS at baseline
    - DOR of high-risk NMIBC (responders only)
    - CR rate at 3 months, CR rates at 6 months, overall CR rate

    All cohorts:
    - PFS, to worsening of grade or stage or death
    - PFS, to muscle-invasive or metastatic disease or death; or
    - OS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Have a histologically-confirmed diagnosis of high risk non-muscleinvasive
    (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 resection is allowed
    -The most recent cystoscopy/TURBT must have been performed within 12 weeks of randomization
    -For Cohort C: subjects with T1 disease should have undergone a restaging TURBT procedure within 12 weeks prior to randomization to confirm complete resection.
    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.) (for cohorts A and B only)
    7. Have adequate organ function.
    8. A female participant is eligible if not pregnant or breastfeeding, and at least one of the following applies:
    - Is not a WOCBP; or
    - Is a WOCBP and using a contraceptive method as described in the
    protocol. A WOCBP must have a negative pregnancy test as described in
    the protocol
    E.4Principal exclusion criteria
    1 . Has centrally-assessed muscle invasive (i.e. T2, T3, T4) locally advanced nonresectable
    or metastatic urothelial carcinoma.
    2 . Has centrally-assessed 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 has had progression or has required active treatment in the last three years
    7. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks
    before randomization/study allocation for Cohort C.
    8. Has severe hypersensitivity to pembrolizumab (all cohorts), MK-7684A (Cohort C arm 1), MK-4280A (Cohort C Arm 2), and/or any of their excipients.
    9. Has an active autoimmune disease that has required systemic treatment in past 2 years
    10. 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 to the first dose of the study intervention. The use of
    physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
    11. Has a history of (non-infectious) pneumonitis/or interstitial lung disease that required steroids or has current pneumonitis.
    12. Has an active infection requiring systemic therapy, including active or intractable UTI in the last month.
    13. Has a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial,
    interfere with the subject's participation, or is not in the best interest of the subject to participate, in the opinion of the investigator.
    14. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the
    requirements of the trial.
    15. 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.
    16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL2 agent, or with an agent directed to another co-inhibitory T-cell receptor
    (e.g. CTLA-4, OX-40, CD137).
    17. Has received previous treatment with another agent targeting the TIGIT and/or LAG3 receptor pathway (Cohort C only).
    18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV- 1/2 antibodies).
    19. Has known active Hepatitis B or Hepatitis C.
    20. Has received a live virus vaccine within 30 days of planned start of trial treatment.
    21. Has had an allogeneic tissue/solid organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    Cohort A and C: 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 and C: 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 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) No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Japan
    Korea, Republic of
    Puerto Rico
    Singapore
    United States
    Finland
    France
    Sweden
    Netherlands
    Spain
    Greece
    Italy
    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 years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    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: 106
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 214
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 79
    F.4.2.2In the whole clinical trial 320
    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 treatment 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 Decision2015-12-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-13
    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
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