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Phase Ib/II study assessing the neo-adjuvant combination therapy of vinflunine with cisplatin followed by radical cystectomy in patients with muscle-invasive bladder cancer (JaNEO).

Inclusion Criteria:

1. Male or female patients aged ≥ 18 years and ≤ 75 years with legal capacity

2. Signed written informed consent

3. Histologically confirmed muscle-invasive urothelial cell carcinoma of the bladder (MIBC) with clinical T2-T4a (N0/Nx, M0) assessed by primary PDD-guided TUR-B and by the screening imaging (MRI pelvis and CT chest/abdomen) which both must include the use of contrast medium

4. Confirmed adequate complete resection of all visible tumor during TUR-B according to current treatment guidelines before registration; the latest TUR-B must have been done ≤ 8 weeks before registration

5. ECOG performance status of 0 or 1

6. Adequate bone marrow, renal and hepatic functions as evidenced by the following:

   • Absolute Neutrophil Count ≥ 2,000 mm3 and ≤ 7,500 mm3
   • Hemoglobin ≥ 12 g/dL for the safety phase of the study; if the study treatment proved to be adequate tolerated during this safety phase, the threshold can be lowered to ≥ 10 g/dL according to the decision of the study steering committee
   • Platelet count ≥ 100,000 mm3
   • Serum albumin within normal range
   • Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
   • Transaminases (ALT, AST) ≤ 1.5 x ULN
   • Creatinine clearance ≥ 60 mL/min, calculated based on a 24h-measured creatinine clearance
   • Serum Urea < 25 mg/100 ml

7. Absence of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; these conditions should be assessed with the patient before registration

8. Electrocardiogram (ECG) without modifications that suggest a high risk of occurrence of an acute clinical event (such as signs of angina pectoris or high-risk arrhythmia, etc.); cardiologist consultation is required, if relevant abnormalities are observed in the screening ECG-assessment

Exclusion Criteria:

1. Prior systemic chemotherapy for any kind of malignancy; prior intravesical chemotherapy or treatment with BCG is allowed

2. Prior radiation of the pelvis or any prior radiation to ≥ 30 % of the bone marrow

3. Evidence of lymph node (N+) or distant metastasis (M1) in the screening imaging assessment, including known brain metastases or leptomeningeal involvement (however, brain-MRI-scans are not required to rule out CNS-involvement, unless there is clinical suspicion of central nervous system (CNS) disease)

4. Any contraindication with regard to contrasted imaging (MRI or CT)

5. Other malignancies except adequately treated basal carcinoma of the skin, localized prostate cancer Gleason ≤ 6, in-situ cervix carcinoma or any other tumor with a disease free interval ≥ 5 years

6. Peripheral neuropathy Grade ≥ 2 NCI CTCAE v4.03 or hearing impairment Grade ≥ 2 NCI CTCAE v.4.03

7. Any concurrent chronic system immune therapy or previous organ allograft

8. Weight loss > 5 % within the last 3 months before registration

9. Any other serious illness or medical condition including:

   • Infection requiring systemic anti-infective therapy within the last 2 weeks before registration
   • History of cardio-vascular disease that might compromise the safe administration of cisplatin
   • Dehydration requiring IV fluid substitution
   • Any medical condition that might not be controlled, e.g. patients with unstable angina pectoris, myocardial infarction < 6 months before registration or uncontrolled diabetes, congestive cardiac failure > NYHA grade I

10. Known hypersensitivity to the study drugs or to drugs with similar chemical structures

11. Treatment with any potent CYP3A4 inhibitor or inductor (e.g. ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicine) or phenytoine; replacement of such treatment with alternative treatment options before start of study treatment is acceptable, if medically feasible and ethically acceptable

12. 12. Treatment with any medication that is known to prolong the QT/QTc interval and/or to cause Torsades de Pointes (e.g. azithromycine, amitryptiline, imipramine, clozapine, flu-ox¬etine, cisapride); replacement of such treatment with alter¬na¬ti¬ve options before start of study treatment is acceptable, if medically feasible and ethically acceptable

13. Treatment with hexamethylmelamin, pyridoxine, penicillamine or any other drug with known potential to affect the efficacy of cisplatin

14. Treatment with any other investigational or anti-cancer therapy ≤ 30 days before registration

15. Pregnant or lactating female patients or female patients of childbearing potential with positive pregnancy test at screening

16. Women of child-bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 6 months after the study

17. Sexually active fertile men, who are unwilling or unable to use an effective birth control from day of informed consent and for up to 6 months after the last cycle of chemotherapy, if their partners are women of child-bearing potential (if cystectomy is not performed) effective birth control means the use of condoms ideally combined with any acceptable contraception of the male patient's partner as described in exclusion criterion 16