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    Summary
    EudraCT Number:2014-002009-40
    Sponsor's Protocol Code Number:MK-3475-045
    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:2014-10-01
    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 number2014-002009-40
    A.3Full title of the trial
    A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) versus Paclitaxel, Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MK-3475 vs. paclitaxel, Docetaxel or vinflunine in metastatic urothelial cancer
    A.3.2Name or abbreviated title of the trial where available
    MK-3475 vs. paclitaxel, Docetaxel or vinflunine in metastatic urothelial cancer
    A.4.1Sponsor's protocol code numberMK-3475-045
    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 pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, PO Box 100
    B.5.3.2Town/ cityWhitehouse Station, NJ
    B.5.3.3Post code0889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1267305 523
    B.5.6E-mailrodolfo.perini@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 1374853-91-4
    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.3.9.4EV 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.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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 name Paclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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: 3
    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 Javlor(R)
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 nameVinflunine
    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 INNVINFLUNINE DITARTRATE
    D.3.9.1CAS number 194468-36-5
    D.3.9.4EV Substance CodeSUB28421
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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: 4
    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 Docetaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameDocetaxel
    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 INNDocetaxel
    D.3.9.1CAS number 114977-28-5
    D.3.9.3Other descriptive nameANHYDROUS DOCETAXEL
    D.3.9.4EV Substance CodeSUB22289
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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: 5
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 name Paclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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
    Metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy
    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 LLT
    E.1.2Classification code 10046714
    E.1.2Term Urothelial carcinoma bladder
    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
    -Evaluate PFS per RECIST 1.1 by blinded independent radiologists’ review of all subjects with recurrent/progressive metastatic urothelial cancer treated with pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or vinflunine.
    -Evaluate the OS of all subjects with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy (recurrent/progressive metastatic urothelial cancer), when treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    -Evaluate the PFS per RECIST 1.1 by blinded independent radiologists’ review of subjects with platinum-refractory recurrent/progressive metastatic PD-L1 positive urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    -Evaluate the OS of subjects with platinum-refractory metastatic or locally advanced/unresectable PD-L1 positive urothelial cancer, when treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    E.2.2Secondary objectives of the trial
    -Evaluate the safety and tolerability profile of MK- 3475 in subjects with recurrent/progressive metastatic urothelial cancer.
    - Evaluate the ORR per RECIST 1.1. by independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    -Evaluate PFS per modified RECIST by independent radiologists’ review of PD-L1 strongly positive, PD-L1 positive, and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    -Evaluate the objective response rate (ORR) per modified RECIST by independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
    Refer to protocol for complete list
    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 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
    Male and Female subjects with recurrent/progressive metastatic urothelial cancer will be enrolled in this trial.
    1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for FBR. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    2. Be ≥18 years of age on day of signing informed consent.
    3. Have histologically or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology. Subjects with non-urothelial cancer of the urinary tract are not allowed.
    4. Have had progression or recurrence of urothelial cancer following receipt of a first-line platinum-containing regimen (e. g cisplatin, carboplatin):
    a. Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease
    or
    b. Received adjuvant platinum-containing therapy following cystectomy for localized muscle-invasive urothelial cancer, with recurrence/progression ≤12 months following completion of therapy.
    or
    c. Received neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer, with recurrence ≤12 months following completion of therapy.
    5. Have received no more than two prior lines of systemic chemotherapy for metastatic urothelial cancer. Subjects for whom the most recent therapy has been a non-platinum-based regimen following progression/recurrence on platinum-based therapy (i.e. third-line patients) are eligible if they have progressed/recurred on their most recent therapy.
    6. Have provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. A newly-obtained biopsy is strongly preferred but not required if archival tissue is adequate for analysis. Adequacy of the archived or freshly-obtained biopsy specimen must be confirmed by the central laboratory during the screening period prior to enrollment.
    7. Have measureable disease based on RECIST 1.1 as assessed by the investigator/site radiologist. Tumor lesions situated in a previously irradiated area are considered measureable if progression has been demonstrated in such lesions.
    8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed within 10 days prior to treatment initiation. Subjects with an ECOG performance status of 2 must have a hemoglobin ≥10 g/dL, must not have liver metastases, and must have received the last dose of their last prior chemotherapy regimen ≥3 months (90 days) prior to enrollment.
    9. Demonstrate adequate organ function as defined in Table 1 of the protocol, all screening labs should be performed within 10 days of treatment initiation
    10. 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    11. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel or vinflunine. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
    12. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab (MK-3475) or 180 days after the last dose of paclitaxel, docetaxel or vinflunine.

    Crossover from Control Arm to Pembrolizumab
    •Have been randomized to the control arm, taken at least one dose and subsequently discontinued treatment with paclitaxel, docetaxel or vinflunine.
    •Experienced an investigator-determined confirmed radiographic disease progression per RECIST 1.1 after stopping their initial treatment.
    •A scan must be performed within 30 days prior to starting treatment with pembrolizumab.
    •Did not receive any anti-PD1/PD-L1, anti-CTLA4 or other checkpoint inhibitor since the last dose of chemotherapy.
    •Have a performance status of 0 to 2 on the ECOG Performance Scale.
    •Subjects with known and treated brain metastasis are eligible provided they are clinically stable, and brain metastases have been treated.
    •Have adequately recovered from adverse events of previous anti-cancer therapy.
    •Female and male subjects should agree to use adequate methods of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
    E.4Principal exclusion criteria
    1.Has disease that is suitable for local therapy administered with curative intent.
    2.Currently participating/ has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose.
    3.Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose. The use of physiologic doses of corticosteroids may be approved.
    4.Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
    5.Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from adverse events due to a previously administered agent.
    6.Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, PSA undetectable.
    7.Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    8.Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s syndrome will not be excluded from the study.
    9.Has active cardiac disease, defined as:
    a. Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy
    b. History of serious ventricular arrhythmia, high-grade AV block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled); history of QT interval prolongation
    c. NYHA Class III or greater congestive heart failure, or left ventricular ejection fraction of < 40%
    10.Has evidence of interstitial lung disease or active non-infectious pneumonitis.
    11.Has an active infection requiring systemic therapy.
    12.Has a history of severe hypersensitivity reaction to paclitaxel or to other drugs formulated with polyoxyethylated castor oil, to docetaxel or other drugs formulated with polysorbate 80,or to vinflunine or other vinca alkaloids.
    13.Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the CYP3A4 enzymes.
    14.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 for the full duration of the trial, or is not in the best interest of the subject to participate.
    15.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    16.Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose.
    17.Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
    18.Has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).
    19.Has a known history of HIV.
    20.Has known active Hepatitis B or C.
    21.Has received a live virus vaccine within 30 days of planned start of trial treatment.
    22.Is/ has an immediate family member who is investigational site or sponsor staff directly involved with this trial.

    Crossover from Control Arm to Pembrolizumab
    • Has discontinued from study MK-3475-045.
    • Has active pneumonitis of Grade 2 or greater or history of pneumonitis requiring systemic steroid therapy.
    • Has received thoracic radiation therapy of > 30 Gy within 6 months have active and untreated brain metastasis.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints are progression-free-survival (PFS) and overall survival (OS) in PD-L1 strongly positive, PD-L1 positive, and all subjects.
    E.5.1.1Timepoint(s) of evaluation of this end point
    OS: The time from randomization to death due to any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up. PFS: The time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent radiologists’ review or death due to any cause, whichever occurs first.
    E.5.2Secondary end point(s)
    -Objective Response Rate (ORR)
    -PFS/ORR
    -Response Duration
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR: When the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based upon blinded central radiologists' review per RECIST 1.1. A supportive analysis of ORR will be conducted using site radiology review as defined in the Imaging Review Charter.
    PFS and ORR : When modified RECIST by blinded independent
    radiologists' review Response Duration: The time from first documented evidence of CR or PR until disease progression or death. Response duration will be calculated for RECIST 1.1 based on blinded independent radiologists' review and site review.
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    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) 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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    Paclitaxel, Docetaxel and Vinflunine
    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 EEA60
    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
    Denmark
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Norway
    Peru
    Poland
    Portugal
    Puerto Rico
    Romania
    Singapore
    Spain
    Sweden
    Taiwan
    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
    The overall trial ends when the last subject completes the last study-related phone call or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 368
    F.4.2.2In the whole clinical trial 470
    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 Decision2014-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-29
    P. End of Trial
    P.End of Trial StatusOngoing
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