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    The EU Clinical Trials Register currently displays   35654   clinical trials with a EudraCT protocol, of which   5853   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2014-003626-40
    Sponsor's Protocol Code Number:CA209-274
    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:2016-02-15
    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 number2014-003626-40
    A.3Full title of the trial
    A Phase 3 Randomized, Double-blind, Multi-center Study of Adjuvant Nivolumab versus Placebo in Subjects with High Risk Invasive Urothelial Carcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nivolumab versus placebo after surgery in subjects with urinary tract cancer
    A.3.2Name or abbreviated title of the trial where available
    CheckMate 274
    A.4.1Sponsor's protocol code numberCA209-274
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1160-7285
    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 SponsorBristol-Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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 supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointGCT-SU
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.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 nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) No
    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 injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    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
    Subjects with High Risk Invasive Urothelial Carcinoma
    E.1.1.1Medical condition in easily understood language
    Subjects who have undergone radical resection of Invasive urothelial carcinoma originating in the bladder or upper urinary tract (renal pelvis or ureter) and are at high risk of recurrence.
    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 10064467
    E.1.2Term Urothelial carcinoma
    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 the disease free survival (DFS) for nivolumab versus placebo in:
    - subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells)
    and
    -all randomized subjects
    E.2.2Secondary objectives of the trial
    -To compare Non-Urothelial Tract Recurrence Free Survival (NUTRFS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects
    -To compare the Disease Specific Survival (DSS) for nivolumab and placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects
    -To compare the Overall Survival (OS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. All subjects must be status post radical surgical resection (R0) for Invasive Urothelial Carcinoma performed within 120 days prior to randomization. Subjects with carcinoma in situ in surgical margins are not eligible for study entry.
    2. All subjects must have pathologic evidence of urothelial carcinoma (originating in bladder, ureter, or renal pelvis) at high risk of recurrence based on pathologic staging of radical surgery tissue (see protocol for more details)
    3. Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (eg. minor variants) are accepted
    4. All subjects must have disease-free status defined as no clinical or radiographic evidence of recurrence of disease documented by a complete physical examination and imaging studies within 4 weeks of randomization. Subjects with equivocal nodes less than 15 mm in short axis may be eligible after discussion with BMS Medical Monitor. All suspect lesions identified during screening radiographic procedures should be discussed with the Medical Monitor prior to randomization. Imaging studies must include CT of chest and CT or MRI of abdomen, pelvis, and all known sites of resected disease including cystoscopy in subjects with upper GU primaries who still have bladder intact. Brain imaging (MRI except where contraindicated in which CT scan is acceptable) must be completed within 4 weeks prior to randomization for subjects with clinical suspicion of CNS disease. Subjects who are found to have high-risk NMIBC at the time of screening are not eligible for study entry.
    Patients with low-risk papillary lesions may enter the study if rendered free of disease at cystoscopy.
    Subjects with intermediate-risk NMIBC may enter the study if intravesical chemotherapy or BCG is not required. Screening cystoscopy may occur within 60 days of randomization and is encouraged to be done prior to other imaging. Any suspect lesions seen on cystoscopy should be biopsied to rule-out the possibility of high-risk lesions.
    5. Tumor tissue from the most recently resected site of disease (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis must be provided for biomarker analyses. In order to be randomized, a subject must have a PD-L1 expression level classification (>=1%, < 1%, indeterminate) as determined by the central lab.
    6. Life expectancy >= 6 months
    7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Subjects who have not received cisplatin based neoadjuvant chemotherapy and are considered ineligible for cisplatin adjuvant chemotherapy, may enter the study with ECOG PS 2 (see Appendix 2)
    8. Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration. TUR must be completed 14 days before randomization.
    E.4Principal exclusion criteria
    1. Partial cystectomy in the setting of bladder cancer primary tumor or partial nephrectomy in the setting of renal pelvis primary tumor.
    2. Adjuvant systemic or radiation therapy for urothelial or prostatic carcinoma following radical surgical resection of urothelial carcinoma.
    3. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
    4. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer with evidence of undetectable Prostate Specific Antigen (PSA) or carcinoma in situ of the prostate, cervix or breast. Patients with known history of recent metastatic urothelial carcinoma will be excluded.
    5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    6. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
    7. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after adrenal crisis).
    8. All toxicities attributed to prior anti-cancer therapy other than nephropathy, neuropathy, hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll. See protocol inclusion criterion 2) i) (5) for renal function eligibility. Neuropathy must have resolved to Grade 2 (NCI CTCAE version 4).
    9. Treatment with any chemotherapy, radiation therapy, biologics for cancer, intravesical therapy, or investigational therapy within 28 days of first administration of study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    Disease Free Survival - This endpoint will be analyzed in two different populations (co-primary): Subjects with PD-L1 expression level >=1% and all randomized subjects.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Approximately 5 years after the first subject is randomized.
    E.5.2Secondary end point(s)
    -To compare Non-Urothelial Tract Recurrence Free Survival (NUTRFS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects
    -To compare the Disease Specific Survival (DSS) for nivolumab and placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects
    -To compare the Overall Survival (OS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For all secondary endpoints: approximately 5 years after the first subject is randomized.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Outcomes Research Assessments, Immunogenicity Assessments
    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 EEA68
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    Denmark
    France
    Germany
    Greece
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Peru
    Poland
    Romania
    Russian Federation
    Spain
    Sweden
    Switzerland
    Taiwan
    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
    Last follow-up visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days25
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 720
    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 state54
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 458
    F.4.2.2In the whole clinical trial 800
    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)
    At the end of the study, BMS will not continue to provide BMS supplied study drug to subjects/investigators unless BMS chooses to extend the study. The study is designed to have a maximum treatment duration of 1 year and at the end of the study no subjects are expected to be on treatment. The investigator should ensure that the subject receives appropriate standard of care to treat the condition under 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 Decision2016-02-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-13
    P. End of Trial
    P.End of Trial StatusOngoing
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