Due to limited experience with cabazitaxel in TCCU, the study will be started as a randomised phase II study. The aim of the phase II study is to evaluate if the response rates (CR + PR) are sufficiently high to further study the treatment regimens in a phase III setting.

Once it is confirmed that the subjects fulfil the eligibility criteria and have signed the informed consent, they will be randomised to receive treatment based on cabazitaxel or vinflunine according to the following study schema:

(Randomize 1:1)

• Cabazitaxel 25 mg/m2 q3w
• Vinflunine 250-320 mg/m2 q3w

Random assignment of treatment will be stratified by the presence of 0 versus 1 of the following unfavourable prognostic risk factors proposed recently by Bellmunt et al. (1):

• Eastern Cooperative Oncology Group (ECOG) PS 1.
• Anaemia with Hb <10 g/dL.
• Presence of liver metastases.

All patients enrolled in the study will receive a cycle of treatment with the study medication (cabazitaxel or vinflunine) every 21 days until disease progression or intolerable/unacceptable toxicity. Tumour evaluations will be scheduled every 6 weeks until progression

Inclusion Criteria:

• Written informed consent

• Histologically confirmed TCCU (urinary bladder, urethra, ureter or renal pelvis). Patients with mixed histology may be enrolled if TCCU is the predominant component (i.e., > 50% of the histopathology sample) with the exception of neuroendocrine or small cell carcinoma.

• Advanced disease defined as a locally advanced tumour considered unresectable (T4b), node involvement in the inguinal area or above the aortic bifurcation (that are considered to be distant nodes and so metastasis) or metastasis in distant organs.

• Patient should have received one prior platinum-based chemotherapy treatment for locally advanced or stage IV TCCU. Prior platinum-based adjuvant or neoadjuvant therapy is allowed if more than 6 months have elapsed since the end of adjuvant or neoadjuvant therapy till tumour relapse.

• At least one measurable tumour lesion (measurable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1

• ≥18 years.

• ECOG PS 0 or 1.

• May have no more than ONE of the following unfavourable risk factors:

  1. haemoglobin <10 g/dL
  2. presence of liver metastasis
  3. ECOG PS 1

• Life expectancy of at least 12 weeks.

• Adequate hematologic, hepatic, and renal function, defined by:

• Females of childbearing potential must have a negative serum pregnancy test within 7 days of study entry.

Exclusion Criteria:

• Patients that have 2 or more of the following unfavourable risk factors:

  1. Haemoglobin <10 g/L
  2. Liver metastasis
  3. ECOG PS 1.

• Women who are currently pregnant or breast-feeding.

• Any unresolved non-hematologic Adverse Event (AE) grade >1 (Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) Version 4.0) from previous anti-cancer therapy (other than alopecia)

• Patients who had undergone major surgery, radiation therapy or treatment with chemotherapy or any investigational agent within 28 days prior to Study day 1.

• Evidence of severe or uncontrolled systemic disease or any concurrent condition

• History of another neoplasm.

• History of hypersensitivity reactions to taxanes (docetaxel) (cabazitaxel specific criteria), vinca alkaloids (vinflunine specific criteria) or to any of the formulation excipients, including polysorbate 80

• clear evidence or symptoms of central nervous system metastasis (cabazitaxel specific criteria).

• Clinically significant cardiac condition