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

Randomized Phase II Study Assessing the Combination of Vinflunine With Gemcitabine and Vinflunine With Carboplatin in Patients Ineligible to Cisplatin With Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium

This study is assessing the combination of well known cytotoxics with a novel anti-cancer agent that could be administered as monotherapy without renal toxicity in patients with renal impairment presenting with advanced or metastatic urothelial carcinoma previously treated with a platinum-based regimen. The intent of this study is to clarify the benefit/risk ratio of the two most promising associations of cytotoxics including the novel therapeutic agent, vinflunine: vinflunine-gemcitabine and vinflunine-carboplatin.

Gemcitabine and carboplatin have been the most studied and used anticancer agents in cisplatin-unfit patients with advanced urothelial carcinoma. Both agents previously demonstrated clinical activity as single agent and/or as part of combination regimen in patients with advanced or metastatic disease even if clinical benefits and survival remains limited in this setting for this population.

The purpose of this study is to test in a randomized trial enrolling patients with renal impairment or moderate congestive heart failure two combinations of a novel cytotoxic agent, vinflunine, one with gemcitabine and another with carboplatin in order to determine the most promising combination in the first line treatment of advanced/metastatic urothelial carcinoma.

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