JAVLOR Association Study in CDDP-unfit Patients With Advanced Transitional Cell Carcinoma: Gemcitabine Versus Carboplatin

Inclusion Criteria:

* Man or woman aged ≥ 18 years and \< 80 years
* Signed written informed consent
* Histologically confirmed diagnosis of locally advanced or metastatic predominantly transitional cell carcinoma of the urothelium (TCCU)
* Ineligibility for cisplatin-based therapy because of at least one of the following two medical conditions:

  * Calculated creatinine clearance (Cockcroft-Gault formula)\< 60 mL/min
  * New York Heart Association Classification Stage II-III Congestive Heart Failure (documented by medical history)
* "Measurable" disease with at least one uni-dimensional lesion according to RECIST guideline (version 1.1)
* ECOG performance status of 0 or 1
* Estimated life expectancy of at least 12 weeks
* Patient without prior systemic anticancer therapy unless if it had been administered as neoadjuvant or adjuvant chemotherapy (CT) for TCCU and if the patient has documented relapse ≥ 6 months after the last dose of CT (prior intravesical CT allowed)
* Adequate bone marrow and hepatic functions as evidenced by:

  * Absolute Neutrophil Count ≥ 2,000/mm3 (≥ 2.0 x 109/L)
  * Haemoglobin ≥ 10 g/dL
  * Platelet count ≥ 100,000/mm3
  * Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  * Transaminases ≤ 2.5 x ULN \[≤ 5 x ULN only in case of liver metastasis\]
* 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 in the trial

Exclusion Criteria:

* ECOG performance status ≥ 2
* Woman if pregnant or lactating or with positive pregnancy test at inclusion; woman of child-bearing potential who did not use or is unwilling or unable to use an acceptable method to avoid pregnancy during the 2 months preceding the start of study treatment, for the entire study period and for up to 3 months after the last dose of study treatment; sexually active fertile man not using effective birth control during the study and up to 6 months after the last dose of study treatment if his partner is a woman of child-bearing potential
* Known brain metastasis or leptomeningeal involvement.
* Peripheral neuropathy Grade ≥ 2 by NCI CTC
* Prior radiation to ≥ 30% of the bone marrow or completed \< 30 days ago or without full recovery of toxicities
* Other serious illness or medical condition including:

  * Infection requiring systemic anti-infective therapy
  * Any medical condition that might not be controlled, for instance patients with unstable angina, patients with myocardial infarction within 6 months or uncontrolled diabetes
* Prior systemic chemotherapy for advanced or metastatic disease or neoadjuvant/adjuvant chemotherapy that was completed \< 6 months before documented progression
* Patient who had received any other investigational drug or anti-cancer therapy within 30 days before randomisation
* Other malignancies except adequately treated basal carcinoma of the skin, in-situ cervix carcinoma, localised prostate cancer with limited risk of recurrence (pT ≤ 2b, Gleason score ≤ 7) that was incidentally discovered and did not lead to any other treatment apart from prostatectomy, or any other tumor with a disease free interval ≥ 5 years
* Inadequate renal function defined by a serum creatinine clearance \< 30 mL/min (Cockcroft-Gault formula)
* Known hypersensitivity to the study drugs or to drugs with similar chemical structures
* Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicin (any potent CYP3A4 inhibitor or inducer) or phenytoin
* Any concurrent chronic system immune therapy or previous organ allograft
* Electrocardiogram (ECG) with significant modifications suggesting a high risk of occurrence of an acute clinical event