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    Summary
    EudraCT Number:2017-000949-53
    Sponsor's Protocol Code Number:OZBS62.14103
    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:2017-04-12
    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 number2017-000949-53
    A.3Full title of the trial
    REduce BlAdder CAncer REcurrence in patients treated for upper urinary tract urothelial carcinoma (REBACARE Trial)
    Verminder blaaskankerrecidief bij patiënten die worden behandeld voor urotheelcarcinoom van de hoge urinewegen (REBACARE studie)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    REduce BlAdder CAncer REcurrence in patients treated for upper urinary tract urothelial carcinoma (REBACARE Trial)
    Verminder blaaskankerrecidief bij patiënten die worden behandeld voor urotheelcarcinoom van de hoge urinewegen (REBACARE studie)
    A.3.2Name or abbreviated title of the trial where available
    REBACARE TRIAL
    REBACARE studie
    A.4.1Sponsor's protocol code numberOZBS62.14103
    A.5.4Other Identifiers
    Name:NL60919.078.17Number:ToetsingOnline
    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 SponsorErasmus MC, Dept. Urology
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKWF Kankerbestrijding
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointCoordinating Investigator
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31107030538n.a.
    B.5.5Fax numbern.a.n.a.n.a.n.a.
    B.5.6E-mailj.boormans@erasmusmc.nl
    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.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameMitomycin
    D.3.4Pharmaceutical form Powder for intravesical solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravesical use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMITOMYCIN
    D.3.9.1CAS number 50-07-7
    D.3.9.4EV Substance CodeSUB09006MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 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 Yes
    D.3.11.13.1Other medicinal product typeMitomycin (also known as Mitomycin C) is an antibiotic isolated from the broth of Streptomyces caespitosus which has been shown to have antitumor activity.
    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
    Upper Tract Urothelial Carcinoma (UTUC).
    Urotheelkanker van de hoge urinewegen.
    E.1.1.1Medical condition in easily understood language
    Upper Tract Urothelial Carcinoma (UTUC).
    Urotheelkanker van de hoge urinewegen.
    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 HLGT
    E.1.2Classification code 10038364
    E.1.2Term Renal and urinary tract neoplasms malignant and unspecified
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10038365
    E.1.2Term Renal and urinary tract therapeutic procedures
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To show that a single intravesical instillation of chemotherapy immediately (<2 hours) before radical nephro-ureterectomy or partial ureterectomy for a urothelial carcinoma of the UUT reduces the risk of a subsequent urothelial bladder cancer recurrence up to two years after surgery with 40% compared with a matched historical cohort who received no perioperative intravesical instillations.
    Aantonen dat een eenmalige intravesicale instillatie met chemotherapie direct (<2 uur) voorafgaand aan een radicale nefro-ureterectomie of gedeeltelijke ureterectomie bij een urotheelcarcinoom van de hoge urinewegen de kans op een latere urotheel blaaskankerrecidief tot twee jaar na de operatie met 40% vermindert in vergelijking met een gematchet historisch cohort die geen peri-operatieve intravesicale instillaties hebben ontvangen.
    E.2.2Secondary objectives of the trial
    To show a ≥80% compliance rate and accurate and consistent protocol performance of a single neoadjuvant instillation with Mitomycin three hours before radical nephro-ureterectomy or partial ureterectomy for a urothelial carcinoma of the UUT. In addition, to assess the 2-year overall, cancer-specific, and recurrence-free survival, the quality of life, and the costs of a single neoadjuvant instillation with Mitomycin before radical nephro-ureterectomy or partial ureterectomy for an UUT urothelial carcinoma compared with no perioperative intravesical instillations. Lastly, a genomic characterization of UUT urothelial carcinoma and subsequent bladder cancer recurrences within the same patients by whole genome sequencing.
    Aantonen van een ≥80% nalevingspercentage en nauwkeurige en consistente uitvoering van het protocol van een enkele neoadjuvante instillatie met Mitomycine drie uur voor radicale nefro-ureterectomie of partiële ureterectomie voor een urotheelcarcinoom van de UUT. Daarnaast het bepalen van de 2-jaars, kankerspecifieke en ziektevrije overleving, de levenskwaliteit en de kosten van een neoadjuvante instillatie met Mitomycine voorafgaand aan radicale nefro-ureterectomie of gedeeltelijke ureterectomie bij een UUT urotheelcarcinoom in vergelijking met geen perioperatieve intravesicale instillaties. Tot slot, genomische karakterisering van UUT urotheelcarcinoom en de daaropvolgende blaaskanker recidieven binnen dezelfde patiënten door whole genome sequencing.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - The following information is included in the main protocol:
    At inclusion, patients will be asked to provide separate consent for the use of their tumor tissue for molecular analysis (both UUT tumor and bladder tumor in case a bladder recurrence occurs). For that purpose, directly after the specimen(s) is removed by surgery, a biopsy will be taken from the tumorous region and DNA will be isolated from the primary UUT tumor, and the subsequent bladder recurrence. Next, whole genome sequencing will be performed to investigate tumor-specific somatic mutations and copy number variations to compare the molecular profile of the primary UUT tumor and subsequent bladder tumor. Germline DNA will be collected by a single buccal swap at inclusion.
    - Separate informed consent form called "Zijstudie voor deelnemers aan de REBACARE studie" ("Side-study for participants in the REBACARE-study"), version 1.0, 23 March 2017.
    E.3Principal inclusion criteria
    - Patients with histologically proven urothelial carcinoma of the UUT with or without concurrent carcinoma in situ (CIS only is also allowed) or patients with a suspicion of a urothelial carcinoma of the UUT on CT-scan with or without a urinary cytology sample suspicious of the presence of high-grade urothelial carcinoma. In case urinary cytology shows no abnormality and no diagnostic URS is done, conclusive results of the CT-urography are sufficient for inclusion and the coordinating investigator will evaluate the eligibility of the subject in consultation with the local investigator.
    - Patients treated either by partial ureterectomy or by a radical nephro-ureterectomy (open or laparoscopic) including a bladder cuff.
    - Age ≥ 18 years.
    - WHO performance status 0,1, or 2.
    - Negative pregnancy test in women with childbearing potential.
    - Written informed consent.
    - Patiënten met histologisch bewezen urotheelcarcinoom van de bovenste urinewegen, met of zonder gelijktijdige carcinoma in situ (CIS alleen mag ook) of bij patiënten met een vermoeden van een urotheelcarcinoom van de bovenste urinewegen op de CT-scan met of zonder een urine-cytologie monster met verdenking op de aanwezigheid van high-grade urotheel carcinoom. Als er geen abnormaliteit wordt gevonden met de urine-cytology en geen diagnostische URS is gedaan, zijn de resultaten van de CT-urografie voldoende voor inclusie en zal de coördinerend onderzoeker in overleg met de locale onderzoeker bepalen of de patient in aanmerking komt voor deelname.
    - Patiënten die behandeld worden met een gedeeltelijke ureterectomie of een radicale nefro-ureterectomie (open of laparoscopisch) met inbegrip van een blaas cuff.
    - Leeftijd ≥ 18 jaar.
    - WHO performance status 0,1 of 2.
    - Negatieve zwangerschapstest bij vrouwen in de vruchtbare leeftijd.
    - Schriftelijke toestemming.
    E.4Principal exclusion criteria
    - If pre-operative histology obtained by biopsy: aberrant histology of the UUT tumor of >50% (adenocarcinoma, small cell carcinoma, squamous cell carcinoma).
    - Postoperative pathological report shows absence of tumor (pT0) or >50% of the UUT tumor shows aberrant histology .
    - History or presence of a malignant tumor or carcinoma in situ of the bladder.
    - History of UUT urothelial carcinoma on the contralateral side or presence of bilateral UUT urothelial carcinoma.
    - Known allergy against Mitomycin.
    - Anticipated adjuvant intravesical treatment with chemo- or immunotherapy.
    - Anticipated adjuvant intravesical treatment with chemo- or immunotherapy following a diagnostic URS.
    - Acute urinary tract infection at the time of inclusion as assessed by urinary culturing.
    - Lymphadenopathy or distant metastases as assessed by preoperative CT-scan of thorax and abdomen.
    - Any other concurrent severe or uncontrolled disease preventing the safe administration of intravesical Mitomycin.
    - Breastfeeding women.
    - Als pre-operatief bepaald d.m.v. histologie van een biopt: afwijkende histologie van de UUT tumor van> 50% (adenocarcinoom, kleincellig carcinoom, plaveiselcelcarcinoom).
    - Postoperatief pathologisch rapport toont de afwezigheid van tumor (pT0)of afwijkende histologie van de UUT tumor van> 50% .
    - Geschiedenis of aanwezigheid van een kwaadaardige tumor of carcinoma in situ van de blaas.
    - Geschiedenis van UUT urotheelcarcinoom aan de contralaterale zijde of aanwezigheid van bilaterale UUT urotheelcarcinoom.
    - Bekende allergie tegen mitomycine.
    - Verwachte adjuvante intravesicale behandeling met chemo- of immunotherapie.
    - Verwachte adjuvante intravesicale behandeling met chemo- of immunotherapie na een diagnostische URS.
    - Acute urineweginfectie bij inclusie, op basis van urinekweken.
    - Lymfadenopathie of metastasen op afstand zoals beoordeeld door pre-operatieve CT-scan van de thorax en buik.
    - Iedere andere gelijktijdige ernstige of ongecontroleerde ziekte waardoor intravesicale toediening van mitomycine niet veilig is.
    - Vrouwen die borstvoeding geven.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point is the bladder recurrence rate (histologically proven urothelial carcinoma) at two years after surgery for an UUT urothelial carcinoma.
    Het primaire eindpunt is het percentage blaasrecidieven (histologisch bewezen urotheelcarcinoom) twee jaar na de operatie voor een UUT urotheelcarcinoom.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two years after surgery.
    Twee jaar na de operatie.
    E.5.2Secondary end point(s)
    1) To show a >80% compliance rate and accurate and consistent protocol performance of treating physicians.
    2) The overall, cancer-specific, and recurrence-free survival at two years after surgery.
    3) The toxicity of the regimen at three months (CTCAE version 4.0).
    4) The quality of life of the subjects will be assessed at inclusion (T0, before surgery and neo-adjuvant treatment), at two weeks (T2) and three months (T3) after surgery. The EQ5D-5L and the EORTC QLQ-C30 will be used.
    5) Costs from a societal perspective using a time horizon of two years. The costs consist of direct costs (e.g., personnel costs of health professionals involved, disorder related medication, disorder related innervations, time duration of hospital, informal care) and indirect costs (productivity loss) associated with each regimen.
    6) Incremental cost-effectiveness ratios. The economic evaluation will be a cost-utility analysis and a cost-effectiveness analysis performed from a societal perspective.
    7) At inclusion, patients will be asked to provide consent on the use of their tumor tissue for molecular analysis. Whole genome sequencing will be performed to investigate tumor-specific somatic mutations and copy number variations to compare the molecular profile of the primary UUT tumor and subsequent bladder tumor.
    1) Tonen van > 80% nalevingspercentage en nauwkeurige en consistente uitvoering van het protocol door de behandelend artsen.
    2) Algehele, kankerspecifieke en ziektevrije overleving twee jaar na de operatie.
    3) Toxiciteit van de behandeling na drie maanden (CTCAE versie 4.0).
    4) Kwaliteit van leven van de deelnemers bij inclusie (T0, vóór de operatie en neoadjuvante behandeling), twee weken (T2) en drie maanden (T3) na de operatie. De EQ5D-5L en de EORTC QLQ-C30 zullen worden gebruikt.
    5) Kosten vanuit een maatschappelijk perspectief met een tijdshorizon van twee jaar. De kosten bestaan uit directe kosten (bijvoorbeeld personeelskosten van de zorgmedewerkers die betrokken zijn, ziekte gerelateerde medicatie en innervaties, tijdsduur van ziekenhuis- en informele zorg) en indirecte kosten (productiviteitsverlies) geassocieerd met elk regime.
    6) Incrementele kosteneffectiviteit ratio's. De economische evaluatie zal een kostenutiliteitsanalyse en een kosten-batenanalyse uitgevoerd vanuit een maatschappelijk perspectief zijn.
    7) Bij inclusie zullen patiënten om toestemming worden gevraagd voor het gebruik van hun tumorweefsel voor moleculaire analyse. Whole genome sequencing zal worden uitgevoerd om de tumor-specifieke somatische mutaties en kopie nummer variaties te onderzoeken en het moleculaire profiel van de primaire UUT tumor en de daaropvolgende blaas tumor te vergelijken.
    E.5.2.1Timepoint(s) of evaluation of this end point
    T0 (before surgery and neo-adjuvant treatment), at two weeks (T2) and three months (T3) after surgery.
    T0 (vóór de operatie en neoadjuvante behandeling), twee weken (T2) en drie maanden (T3) na de operatie.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned15
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 end of the study is defined as the last patient’s last visit.
    Het einde van de studie is gedefinieerd als de laatste visite van de laatste patient.
    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 months6
    E.8.9.1In the Member State concerned 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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state170
    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 (standard care).
    Geen (standaard zorg).
    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 Decision2017-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-16
    P. End of Trial
    P.End of Trial StatusOngoing
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