A Trial With Vinflunine in Patients With Metastatic Bladder Cancer and Impaired Renal Function

• Signed informed consent.
• Histological or cytological confirmed transitional cell carcinoma of the urothelial tract (mixed histology including transitional cell carcinoma are allowed).
• Non-curable unresectable (T4b), locally advanced (lymph node positive (N+)) or metastatic (M1) urothelial carcinoma (including renal pelvic tumours, ureteral tumours, urinary bladder tumours and urethral primary tumours).
• No prior antineoplastic chemotherapy or other anti-cancer drugs. Patients who have received neoadjuvant or adjuvant platinum containing chemotherapy and who are diagnosed with loco regional recurrent or metastatic disease after 6 months are eligible.
• Creatinine clearance 30 - 60 ml/min (measured by Iohexol or Cr-EDTA technique)

• ECOG/WHO Performance Status (PS) 0-1.

  •≥ 4 weeks since prior major surgery, ≥ 2 weeks since prior minor surgery (i.e. TUR-B) and ≥ 1 week since prior radiation therapy.

• Measurable and/or non-measurable disease using the RECIST v 1:1 criteria defined as:

  • Measurable disease: lesions that can be measured in at least one dimension and which have not been previously irradiated. Longest diameter ≥10 mm or lymph nodes ≥15 mm in short axis with CT scan or MRI.
  • Non-measurable disease: lesions which have not been previously irradiated, longest diameter \<10 mm or lymph nodes 10-14 mm in short axis with CT scan or MRI, or truly non measurable lesions including bone lesions, ascites, pleural/pericardial effusion, and lymphangitis cutis/pulmonitis.
• CNS metastases and/or leptomeningeal metastases are allowed provided these have been adequately treated with radiotherapy, are stable and not generating any related neurological symptoms.
• Spinal cord compression due to metastatic lesions is allowed provided adequate surgery and/or radiotherapy has been delivered, the metastases are stable and not generating any related neurological symptoms.
• No known or suspected allergy to the investigational agents or any agents given in association with this trial.
• 18 years of age or older.
• Fertile men and women of childbearing potential must use secure contraception (women - intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), men - condom and for a female partner as described above) from before 2 months entering the study until 6 months after end of chemotherapy.

Exclusion Criteria

• Not fulfilling inclusion criteria as described above
• Pure non-transitional cell carcinoma of the urothelial.
• Pronounced hematuria in need of repeated blood transfusions, palliative radiotherapy to the bladder or palliative resection (TUR-B).
• Impaired bone marrow function defined as WBC \< 3.0 x 109/L, neutrophils \< 1.5 x 109/L, platelets \< 125 x 109/L, haemoglobin \< 100 g/L.
• Impaired liver function defined as serum bilirubin > 1.5 x upper limit of normal (ULN) and/or ASAT/ALAT > 2.5 x ULN (> 5 x ULN if known liver metastasis).
• Electrocardiogram (ECG) with significant modifications suggesting a high risk of occurrence of angina pectoris or high risk of arrhythmia.
• Other malignancies, except adequately treated basal carcinoma or squamous cell carcinoma of the skin or in-situ cervix carcinoma or incidental prostate cancer (T1a, Gleason score ≤ 6, PSA \< 0.5 ng/ml), or any other tumour with a disease free survival of ≥ 5 years.

• History of serious or concurrent illness or uncontrolled medical disorder; any medical condition that might be aggravated by chemotherapy treatment or which could not be controlled; including, but not restricted to:

  • Active infection requiring antibiotics within 2 weeks before the study inclusion,
  • Unstable diabetes mellitus,
  • Hypercalcaemia >2.9 mmol/L (grade ≥ 2 according to CTCAE v 4.0),
  • Concurrent congestive heart failure NYHA (class III-IV),
  • Unstable angina pectoris, or myocardial infarction within 6 months and/or poorly controlled hypertension,
  • QTc > 450 ms at baseline,
  • Inflammatory bowel disease,
  • Peripheral neuropathy grade ≥ 2 according to CTCAE v 4.0,
• Patients who require treatment with ketoconazole, fluconazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicin (any potent CYP3A4 inhibitor or inducer) or phenytoin.
• Pregnant or lactating women.
• Any psychological, familial, sociological, or geographical condition which does not permit protocol compliance and medical follow-up.