Study Synopsis


Titel of Study	BRIDGing the Gap between Clinical and Molecular Data – in Clinical Routine Registers in Bladder Cancer (“Bladder BRIDGister”)
Indication	Patients with low &high risk pTa NMIBC, pT1 NMIBC & MIBC – All-Comers Design to assess Real World Experience
Study Type	Open, non-interventional, prospective, multi-center clinical research platform to enable adaptive phase II / III clinical trials
Preparation of Synopsis	Urology PD Dr. Thorsten Ecke (Bad Saarow / Berlin) Molecular Pathology Dr. Ralph M. Wirtz (Köln) Pathology PD. Dr. Sebastian Eidt (Köln) PD. Dr. Ergin Kilic (Leverkusen, Köln)
Rationale	In the advent of molecular testing and subsequent molecular targeting of bladder cancer a detailed knowledge of treatment reality comprising histopathological and molecular characteristics (subtypes, mutations, immune infiltrates) in relation to outcome parameters (response, survival, QoL) and costs is crucial evaluate and improve the quality of care for patients with bladder cancer. The purpose of the BRIDGE Clinical Routine Register (BRIDGister) is to set up a national clinical research platform to document uniform data on the molecular testing, treatment, course of disease in patients with early, advanced or metastatic bladder cancer amenable or not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of any therapy based on transurethral resection biopsies (TUR), urine and blood testing. The data shall be used to assess the current state of care, to catch-up recent developments, document efficacy in real world setting in order to develop recommendations in tight collaboration with S3 guideline KOL’s concerning topics that could be improved and implemented. The BRIDGister consolidates pre-existing platforms for decentral and central biomarker testing, data management and tissue, urine and blood repositories, that have been validated in core cooperations in the past 10 years as part of retrospective and prospective trials. With its passion for precision oncology performed on highly standardized molecular testing in conjunction with centralized histopathological re-evaluation in multidisciplinary teams. The BRIDGister enables fast and interactive access to clinically characterized patient cohorts and bears potential subsequent prospective trials.
Objectives	To assess molecular biomarker testing, treatment and outcome of patients with high risk pTa NMIBC, pT1 NMIBC & MIBC in Germany, in particular: To collect high quality, validated data on the frequency, methodology and results of decentral histopathological and biomarker testing To harmonize data collection by standardized biomarker retesting at specialized high-volume treatment centers To establish a clinically annotated bio-repository (TUR biopsies and cystectomies) To collect real-world clinical data in high-volume treatment centers and beyond: To describe systemic treatments and sequential treatments applied in real-life practice To assess efficacy of loco-regional (e.g. instillation) and systemic treatments in regards to general and specific outcome parameters such as response rate, recurrence free survival, progression free survival and overall survival To assess sensitivity and specificity of protein based and molecular assessment of urine testing including uBIOM assessment across all stages and in comparsion to healthy controls Safety of current treatment approaches To describe physician-reported factors affecting treatment decision making besides histopathological assessment and biomarker profiling to investigate changes in diagnostics, treatment or outcome during the course of the project and implementation of new drugs upon approvals to collect PRO and QoL measures to provide a test und research platform for biomarker-stratified adaptive clinical trials for recurrent NMIBC and metastasized MIBC
Feasibility considerations: Target population, number of patients/accrual goal and sites	Target population: Patients with locally early, advanced or metastatic bladder cancer at the start of the first therapy. In Germany, approximately 36,000 patients have been newly diagnosed with bladder cancer in 2018, of whom 7,000 patients presented with pTa high risk or pT1 NMIBC and 12,000 patients had advanced disease [Ferlay et al. GLOBOCAN 2019]. The BRIDGister has been initiated in Q3/2020 in cooperation with the Urology of the Helios Hospital in Bad Saarow. After platform consolidation in Q1/2 2021 it shall be rolled out into 7 centers (university clinics, clinical centers and circumscribed urology networks) with a total of >2,100 newly diagnosed bladder cancer patients per year, summing up to >10,500 patients over the project period of 5 years. Potential patients are expected to segregate according to tumor stage with a ratio of ~ 7,350 NMIBC cases to 3,150 MIBC cases. Approximately 50% (~4,600) of these patients will be tested for molecular alterations according to the individual risk of recurrence or death. Assuming that 70% of these molecularly tested patients consent to BRIDGister participation, the registry will be able to accumulate ~3,200 molecularly characterized high risk NMIBC and MIBC patients at initial diagnosis. The BRIDGister will additionally enroll patients with untested bladder cancer (BRIDGister satellite patients) up to a total accrual goal of ~9,000 registered patients. Patient recruitment may be extended into additional sites (certified cancer centers, comprehensive cancer centers, hospitals and office-based oncology practices) in Germany.
Study Infrastructure	Study logistics and data management (STRATIFYER, CLIMEDO) Clinical trial centers and pathology labs at academic institutions Central histopathological and cytology testing at reference pathology (Cologne) Monitoring and documentation by STRATIFYER
Main inclusion and exclusion criteria	Main inclusion criteria: Written informed consent for all study procedures before data acquisition must be obtained and documented according to the local regulatory requirements Histologically confirmed NMIBC, MIBC or mBC Age ≥ 18 years All ECOG stages plus Charlson Comorbidity Index Main exclusion criteria: None
Data Collection	Baseline (demographic, clinical, tumor) characteristics, details on biomarker testing, including re-testing, treatment decision making, all systemic anticancer therapies including details, key data on radiotherapies, instillations, surgeries, systemic treatments in the curative an palliative settings, outcome (response, progression, survival), course of disease. Data will be documented at baseline and updated at least every three months.
Clinical endpoints	To describe systemic treatments and sequential treatments applied in real-life practice To describe sensitivity/specificity and prognostic/predictive value of protein- as well as molecular urine testing including microbiome characterization To assess efficacy of loco-regional (e.g. instillation) and systemic treatments in regards to general and specific outcome parameters such as response rate, recurrence free survival, progression free survival and overall survival Safety of current treatment approaches To describe physician-reported factors affecting treatment decision making besides histopathological assessment and biomarker profiling
Morpho-molecular endpoints /Histopathological and molecular testing	Histological type WHO grade (1973 & 2004/2016) Locoregionary tumor stage, tumor size, nodal status (incl. node count), lympho-vascular infiltration, blood vessel invasion, perineurial sheeth invasion Standardized assessment of variant urothelial histology; standardized assessment of histology other than urothelial (Adenocarcinoma, pure SCC, neuroendocrine carcinomas) Site of initial and subsequent metastasis Urine testing (NMP22, BTA stat, Uromonitor, uBIOM) FGFR mutation/fusion status Immune cell infiltration by histopathology and molecular testing PD-L1 status by IHC & RT-qPCR Bladder Cancer mutation panel Molecular subtype defined by IHC & RT-qPCR Target gene quantitations by BladderTyper RT-qPCR
Statistics	Descriptive and exploratory statistics will be performed as described in the statistical analysis plan.
Reports / Publications	every 6 months progress reports; i.e. accrual and epidemiological report yearly full reports on treatments administered and clinical outcomes yearly full reports on biomarker testing and retesting specialized reports on sub-analysis / exploratory biomarker test etc. upon request Continuous abstract submission for major urological /oncology meetings (ASCO GU, EAU, ESMO, ASCO, DGU) and publication Subsequent publication in peer-reviewed journals in the main topics (epidemiology, molecular subtyping and outcome prediction by tissue based assessment, matched tissue / urine analytics, mutation detection and monitoring in urine, microbiome characterization and dynamic changes thereof pre/post therapy, identification and quantification of new therapy targets for nuclear medicine approaches) according to a publication plan with quarterly status updates.
Number of Patients / site	approx. 300 evaluable patients per year per site Non-Competitive recruitment
Enrolment Period	Run-in phase: Enrolment start / FPI: Q III 2020 all sites active: Q III 2021 Accrual phase: Full capacity enrolment start: Q IV 2021 Enrolment stop: Q IV 2025
Contact details	Concept, Project Management and Analyses: STRATIFYER Molecular Pathology GmbH, Cologne Dr. Ralph. M. Wirtz, Ralph.Wirtz@STRATIFYER.de
Administrative Aspects	The present research project is an investigator initiated non-interventional prospective registry which will be conducted according to the Declaration of Helsinki, local legal requirements and European data privacy protection laws (GDPR). The CRO is fulfilling the role of operations lead (similar to a legal sponsor of a clinical trial).
Monitoring and inspections	The study will be monitored by the operations lead (CRO) with primary focus on regulatory compliance and data quality assurance. Both remote and on-site strategies will be implemented.
Patient informed Consent	Informed consent will be obtained from all participating patients by means of oral and written information provided by the investigator and appropriately trained staff. All patients/subjects willing to participate must give written and dated informed consent. The ICF will also be signed by the investigator. The patient will be provided with a copy of the signed informed consent statement. Verification of a signed informed consent statement will be noted on the patient’s study case report form and is subject to verification by on-site monitoring visits. The patient may withdraw from the study at any time without prejudicing future medical treatment. Depending on the nature of the withdrawal (full or partial) all acquired data must be removed from the study database according to current GDPR provisions.
	Ethics and regulatorary considerations The study described in this protocol will be conducted in compliance with the Declaration of Helsinki, the professional code of conduct for physicians in Germany (Berufsordnung) and applicable regulatory regulations (e.g. GDPR) in all aspects of preparation, monitoring, reporting, auditing and archiving. The final approved protocol and the informed consent statement will be reviewed by a properly constituted Ethics Committee/Institutional Review Board (IRB). The Ethics Committee’s/IRB final recommendations concerning the conduct of the registry will be made in writing to the investigator. The investigator will agree to make required progress reports to the Ethics committee/IRB, The Ethics Committee/IRB must be informed by the investigator of the termination of the study. The operations lead is responsible for the notification of the study to the regulatory authorities.
Declaration of Helsinki	This study is to be performed in accordance with the Declaration of Helsinki (1964 and current revisions, i.e. 64. WMA 2013 Fortaleza).

Study Synopsis

Study Synopsis

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