A Study Evaluating Chemotherapy With Fractionated Cisplatin/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function.

Randomized, Multicenter, Phase II/III Study, Evaluating Fractionated Cisplatin Chemotherapy/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function.

This is a phase II/III, multicenter, randomized study which includes 420 patients on six years + 3 years follow up. 92 patients will be included during the phase II ; additional 328 patients will be included.

Patients with an advanced or metastatic urothelial cancer with impaired renal function will be randomized in one of the two following chemotherapy arm:

• Fractionated Cisplatin + Gemcitabine.
• Carboplatin + Gemcitabine.

The main objective of the part II study will be to evaluate the efficacy and the safety of a chemotherapy with a doublet platinum salt compound/Gemcitabine with fractionated Cisplatin or Carboplatin in this population.

The main objective of the part III study will be to compare the efficacy in terms of overall survival of a chemotherapy with a doublet platinum salt/Gemcitabine with fractionated Cisplatin or Carboplatin in this population.

Inclusion Criteria:

1. . Age < or = 18 years, patients aged 75 years or more will benefit from a geriatric assessment.
2. . Advanced or metastatic urothelial cancer confirmed histologically or cytologically.
3. . Patients liable to receive a first -line chemotherapy for advanced or metastatic urothelial carcinoma.
4. . Measurable disease according to RECIST criteria V1.1.
5. . Patients who received neoadjuvant or adjuvant chemotherapy based on platinum salt must have completed treatment at least 6 months before entering the study.
6. . Performance status < or = 2.
7. . Life expectancy > 3 months.
8. . Patients with creatinine clearance between 40 and 60 ml / min ( according to Cockcroft and Gault ).
9. . Patients having no contra-indication to overhydration.
10. . Satisfactory hematological tests: Neutrophils > 1.5 G / l Platelets > 150 G / l , hemoglobin ≥ 10 g / dl.
11. . Satisfactory liver function tests: total bilirubin < 1.5 x ULN (upper limit of normal), AST (aspartate aminotransferase) and ALT (alanine aminotransferase)<or = 2.5 x ULN (or 5 x ULN if liver metastases).
12. . In case of prior radiotherapy, a minimum of 14 days must relapse between the end of radiotherapy and study entry.
13. . For women of childbearing age , use an effective contraceptive method to study entry and for the duration of the study and 6 months after the last dose of study treatment ; For sexually active fertile men having a partner of childbearing age using effective contraception for the duration of the study and 6 months after the last dose of study treatment.
14. . Patient affiliated to a social security system in France.
15. . Patient signed informed consent before inclusion in the study and before any specific procedure for the study.

Exclusion Criteria:

1. . Any concomitant or previous malignancy within 5 years prior to the study ( with the exception of basal cell or squamous cell carcinoma in situ).
2. . Pregnant or lactating women.
3. . Patients with brain metastases or meningeal or symptoms suggestive of such secondary locations.
4. . Bisphosphonate or Denosumab treatment initiated within 28 days prior to randomization into the study or patient who have started such treatment during the study ( a bisphosphonate or denosumab treatment initiated within a period longer than 28 days before randomization may be continued without change during the study ).
5. . Other concomitant cancer (radiation therapy, radiopharmaceutical agent chemotherapy).
6. . Patients with uncontrolled infection.
7. . Patients with peripheral neuropathy grade> 1, whatever the origin or patients with hearing loss.
8. . Patient with unstable disease (eg: unstable diabetes, poorly controlled hypertension , congestive heart failure or myocardial infarction within 3 months prior to study entry).
9. . Known hypersensitivity to study drugs.
10. . Treatment with any other investigational drug within 30 days before inclusion.
11. . Any psychological condition , familial, sociological or geographical not to comply with medical monitoring and / or procedures in the study protocol.
12. . Patient protected by law.