E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
muscle invasive urothelial cancer (MIUC) |
muskelinvasives Urothelkarzinom |
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E.1.1.1 | Medical condition in easily understood language |
muscle invasive urothelial cancer (MIUC) |
muskelinvasives Urothelkarzinom |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective is to demonstrate that the addition of neoadjuvant and adjuvant immunotherapy with durvalumab to standard neoadjuvant chemotherapy (with cisplatin/gemcitabine) and surgery in urothelial carcinoma could improve event-free survival. |
Ziel dieser Studie ist nachzuweisen, dass eine neoadjuvante und adjuvante Immuntherapie durch Durvalumab kombiniert mit neoadjuvanter Chemotherapie (mit Cisplatin/Gemcitabin) und Operation das ereignisfreie Überleben verbessert. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Translational Research - Determination of a pre- and post-therapeutic "Tumor immune profile"
in this sub-study we aim to:
- compare the tumor immunome before (treatment-naive) and after neoadjuvant chemo- and immunotherapy
- investigate efficacy outcome parameters in relation to tissue expression of PD-L1
- investiage biomarkers for anti-PD-L1 treatment and their relation to efficacy endpoints of interest (ypT0, EFS and OS) in urothelial carcinoma
- investigate the role of DNA repair pathway alterations in urothelial carcinoma treated with neoadjuvant chemotherapy and immunotherapy
2. Microbiome (optional)
In this sub-study we aim to:
- confirm the hypothesis that the gut microbiota is required for the anticancer effects of PD-L1 Blockade
- validate the relevance of the gut microbiota composition for efficacy of immune checkpoint inhibitors
- understand how immune checkpoint inhibition changes the host microbiome and how these changes correlate with the response of the disease to therapy |
1. Translationale Forschung - "Tumorimmunprofil"
In dieser Substudie:
- sollen das Tumorimmun vor (behandlungsnaiv) und nach der neoadjuvanten Chemo- und Immuntherapie verglichen werden.
- sollen Parameter der Wirksamkeit im Verhältnis zur Gewebsexpression von PDL1 untersucht werden
- sollen Biomarker der Anti-PD-L1 Behandlung und ihre Beziehung zu den Wirksamkeitsendpunkten (ypT0, EFS und OS) im Urothelkarzinom untersucht werden
2. Mikrobiom (optional)
In dieser Substudie:
- Bestätigung der Hypothese, dass die Darmflora für den Antitumoreffekt der PD-L1 Blockade von Bedeutung ist
- soll die Relevanz der Darmflorazusammensetzung für die Wirksamkeit des Immun-Checkpoint-Inhibitors gezeigt werden
- soll untersucht werden, wie die Blockade des Immun-Checkpoints die Zusammensetzung des Mikrobioms verändert und wie diese Änderungen mit dem Ansprechen der Erkrankung auf die Therapie korrelieren |
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E.3 | Principal inclusion criteria |
- histologically proven urothelial cell carcinoma of the bladder, urethra or upper urinary tract and considered suitable for curative multimodality treatment including surgery by a multidisciplinary tumor board
- all histological subtypes eligible if urothelial carcinoma predominant
- WHO performance Status 0-1
- adequate bone marrow, hepatic, renal and cardiac function |
- Histologisch bestätigtes Urothelkarzinom ≥T2 (≤N1, M0) der Blase, Harnröhre, oder des oberen Harntrakts, als geeignet eingestuft für die kurative multimodale Behandlung inklusive Operation durch ein multidisziplinäres Tumor-Board
- Alle histologischen Subtypen sind geeignet, wenn das Urothelkarzinom vorherrschend ist
- WHO Performance Status (Allgemeinzustand) 0-1
- adäquate Knochemarksfunktion, Leber- Nieren- Herzfunktion |
|
E.4 | Principal exclusion criteria |
- pathological evidence of small-cell carcinoma component
- presence of distant metastasis
- previous Treatment with a PD-1 or PD-L1 Inhibitor, including durvalumab
- current or prior use of immunosuppressiva medication within 28 days prior to Registration
- active or prior documented autoimmune or inflammatory disorders
- known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B virus infection |
• pathologischer Nachweis einer kleinzelligen Karzinomkomponente
• Vorhandensein von Fernmetastasen
• Jegliche Vorbehandlung mit einem PD-1- oder PD-L1-Inhibitor, inklusive Durvalumab
• Aktuelle oder frühere Therapie mit immunsupprimierenden Medikamenten innerhalb von 28 Tagen vor Registrierung
• Aktive oder frühere dokumentierte Autoimmunerkrankungen oder entzündliche Erkrankungen
• Medizinische Vorgeschichte einer Infektion mit Humanem Immundefizienz-Virus (HIV) oder aktiver chronischer Hepatitis C oder Hepatitis B Virusinfektion |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint of the trial is event-free survival (EFS) at two years after trial treatment start (neoadjuvant). EFS is defined as the time from treatment start until one of the following events, whichever comes first:
- progression during neoadjuvant treatment is leading to inoperability
- recurrence of locoregional disease after surgery
- appearance of metastases at any localization
- death |
Der primäre Endpunkt ist das ereignisfreie Überleben (EFS) nach 2 Jahren Studienbehandlung (neoadjuvant).
EFS ist definiert als Zeitraum vom Behandlungsbeginn bis zu einem der folgenden Ereignisse:
• Progression während der neoadjuvanten Behandlung, die zu Inoperabilität führt
• Rezidiv der lokoregionären Erkrankung nach Operation
• Auftreten von Metastasen (jeglicher Lokalisation)
• Tod
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
two years after treatment start |
zwei Jahre nach Behandlungsstart |
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E.5.2 | Secondary end point(s) |
- Event free survival (EFS)
- recurrence-free survival (RFS) after R0 resection
- Overall survival (OS)
- Quality of resection
- Pathological complete response rate (ypT0)
- Pathological response rate (PaR) defined by pathological downstaging to ≤ypT1N0M0
- Pattern of recurrence
- Treatment feasibility
- Adverse events |
• Ereignisfreies Überleben (EFS)
• Progressionsfreies Überleben (RFS) nach R0-Resektion
• Gesamtüberleben (OS)
• Qualität der Resektion
• Pathologische Gesamtansprechrate (ypT0)
• Pathologische Ansprechrate (PaR) definiert durch pathologisches Downstaging bis ≤ypT1N0M0
• Rezidivmuster
• Durchführbarkeit der Behandlung
• Unerwünschte Ereignisse
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
at every study visit |
Bei jeder Studienvisite |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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LPLV - last patient last visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |