A randomised Phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium

1) The patient has given written informed consent stating that he or she understands the
purpose of the study and the procedures involved and agrees to participate in the study.
2) The patient has histologically confirmed TCCU (urinary bladder, urethra, ureter or renal
pelvis). Patients with mixed histology may be enrolled if transitional cell carcinoma is the
predominant component (i.e., > 50% of the histopathology sample), with the exception of
neuroendocrine or small cell carcinoma.
3) The patient has advanced disease defined as a locally advanced tumour considered to
be 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.
4) The 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.
5) The patient has at least one measurable tumour lesion (measurable disease, as defined
by the RECIST criteria v1.1), for the phase II part of the study. If all sites of measurable
disease have been irradiated, one site must have demonstrated growth after irradiation.
For phase III part, patients with only non measurable disease are allowed for enrolment.
6) Age >=18 years.
7) ECOG PS 0 or 1.
8) The patient may have no more than ONE of the following unfavourable risk factors:
a) haemoglobin <10 g/dL
b) presence of liver metastasis
c) ECOG PS 1
9) Life expectancy of at least 12 weeks.
10) Adequate hematologic, hepatic, and renal function, defined by:
a) Platelet count >=100 x109/L
b) Absolute neutrophil count (ANC) >1.5x109/L
c) Serum creatinine <=1.5 times the upper limit of normality (ULN). If creatinine
1.0-1.5 xULN, creatinine clearance will be calculated according to Chronic Kidney
Disease Epidemiology group (CKD-EPI) formula and patients with creatinine
clearance <60 mL/min should be excluded
d) Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT) and
alkaline phosphatase (AP) <=2.5 ×ULN (<5 ×ULN in the presence of liver metastasis),
and serum total bilirubin <=1.0 ×ULN.
11) Females of childbearing potential must have a negative serum pregnancy test within 7
days of study entry. Patients of childbearing potential who participate in this study must
use effective contraceptive methods (e.g., abstinence, intrauterine device, oral or
injectable contraceptives, a double barrier method or surgical sterility) to prevent
pregnancy starting as soon as the informed consent form is signed and continuing for at
least 13 weeks after the last dose of the study medication is administered

1) Patients that have 2 or more of the following unfavourable risk factors:
a) Haemoglobin <10 g/L
b) Liver metastasis
c) ECOG PS 1
2) Women who are currently pregnant or breast-feeding.
3) Any unresolved non-hematologic AE grade >1 (NCI-CTCAE, Version 4.0) from previous
anti-cancer therapy (other than alopecia).
4) Patients who had undergone major surgery, radiation therapy or treatment with
chemotherapy or any investigational agent within 28 days prior to Study day 1.
5) Evidence of severe or uncontrolled systemic disease or any concurrent condition
(including uncontrolled diabetes mellitus) which in the Investigator*s opinion makes it
undesirable for the subject to participate in the study or which would jeopardize
compliance with the protocol.
6) History of another neoplasm. Patients with prior history of either non-metastatic
non-melanoma skin cancers; carcinoma in situ of the cervix; or cancer cured by surgery,
small field radiation or chemotherapy >=3 years prior to randomisation; or treated patients
with early stage and low risk prostate cancer (<=pT2 N0 M0, Gleason <=6 and PSA <=0.5
ng/mL) at study entry will be eligible.
7) 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 (cabazitaxel specific criteria).
8) Patients with clear evidence or symptoms of central nervous system metastasis
(cabazitaxel specific criteria).
9) Clinically significant cardiac condition demonstrated by myocardial infarction or
thromboembolic events in the 6 months prior to the study treatment initiation, serious or
unstable angina pectoris, New York Heart Association (NYHA) class III or IV congestive
heart failure, or left ventricular ejection fraction (LVEF) < 50% at baseline (see Appendix
VI) (vinflunine specific criteria).
10) Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome
P450 3A4/5 (a one week wash-out period is necessary for patients who are already on
these treatments) (see Appendix XII).