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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Advanced Urothelial Cancer, Metastatic Urothelial Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Fractionated Cisplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: . Age < or = 18 years, patients aged 75 years or more will benefit from a geriatric assessment. . Advanced or metastatic urothelial cancer confirmed histologically or cytologically. . Patients liable to receive a first -line chemotherapy for advanced or metastatic urothelial carcinoma. . Measurable disease according to RECIST criteria V1.1. . Patients who received neoadjuvant or adjuvant chemotherapy based on platinum salt must have completed treatment at least 6 months before entering the study. . Performance status < or = 2. . Life expectancy > 3 months. . Patients with creatinine clearance between 40 and 60 ml / min ( according to Cockcroft and Gault ). . Patients having no contra-indication to overhydration. . Satisfactory hematological tests: Neutrophils > 1.5 G / l Platelets > 150 G / l , hemoglobin ≥ 10 g / dl. . 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). . In case of prior radiotherapy, a minimum of 14 days must relapse between the end of radiotherapy and study entry. . 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. . Patient affiliated to a social security system in France. . Patient signed informed consent before inclusion in the study and before any specific procedure for the study. Exclusion Criteria: . Any concomitant or previous malignancy within 5 years prior to the study ( with the exception of basal cell or squamous cell carcinoma in situ). . Pregnant or lactating women. . Patients with brain metastases or meningeal or symptoms suggestive of such secondary locations. . 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 ). . Other concomitant cancer (radiation therapy, radiopharmaceutical agent chemotherapy). . Patients with uncontrolled infection. . Patients with peripheral neuropathy grade> 1, whatever the origin or patients with hearing loss. . Patient with unstable disease (eg: unstable diabetes, poorly controlled hypertension , congestive heart failure or myocardial infarction within 3 months prior to study entry). . Known hypersensitivity to study drugs. . Treatment with any other investigational drug within 30 days before inclusion. . Any psychological condition , familial, sociological or geographical not to comply with medical monitoring and / or procedures in the study protocol. . Patient protected by law.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carboplatin/Gemcitabine<br> | Drug: Carboplatin<br>* Carboplatin AUC (area under curve) 4,5 at day 1 of each cycle until 6 cycles.<br>Drug: Gemcitabine<br>* Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.<br>|
| Experimental: Fractionated Cisplatin/Gemcitabine<br> | Drug: Fractionated Cisplatin<br>* Cisplatin 35mg/m² at day 1 and day 8 of each cycle until 6 cycles.<br>Drug: Gemcitabine<br>* Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Efficacy - Rate of non progression at the end of treatment (C6D21). | Progression is defined according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria V1.1. | 5 years. | 
| Phase III: Overall survival (in months). | Overall survival is defined as the time from randomization until death or last follow up news (censured data). | 9 years. | 
| Phase II: Tolerance - Percentage of patients for whom at least one of the 3 defined tolerance criteria (see description) is observed. | Defined tolerance criteria : Postponement of chemotherapy > or = 2 weeks. Alteration of renal function. Need to decrease twice Gemcitabine dose on day 1 for : NCI CTC (National Cancer Institut Common Toxicity Criteria) grade III or IV non-hematologic toxicity, hematologic toxicity. | 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II and III: Objective response. | Objective response (ie complete or partial response) will be evaluated according to RECIST v1.1 criteria. | Phase II: 5 years ; Phase III: 9 years. | 
| Phase II and III: Tolerance according to NCI toxicity scale (version 4.0). |  | Phase II: 5 years ; Phase III: 9 years. | 
| Phase II and III: Geriatric evaluation using questionnaires. | The geriatric assessment will be evaluate using the following questionnaires: G8 (oncodage) , ADL (activity of daily living), CIRSG (cumulating illness rating scale geriatric) , MMS (mini-mental score), IADL (instrumental activities of daily living), GDS (geriatric depression scale), MNA (mini-nutritional assessment). | Phase II: 5 years ; Phase III: 9 years. | 
| Phase II and III: Quality of life using the EORTC QLQ - C30 questionnaire (European Organization for research and treatment of Cancer - Quality of life questionnaire). |  | Phase II: 5 years ; Phase III: 9 years. | 
| Phase II and III: Pharmacokinetics - Platin concentrations |  | At cycles 1 and 2 day 1 - 5 mn before the end of infusion, one hour after the end of infusion, 3 hours (arm A) or 4 hours (arm B) after the end of infusion. | 
| Phase II and III: Pharmacogenetics, exploration of cytidine deaminase activity and study of its genetic polymorphisms. |  | Prior to the initial dose on cycle 1 day 1. | 
| Phase II and III: Progression free survival. | Progression free survival will be evaluated according to RECIST v1.1 criteria. | Phase II: 5 years ; phase III: 9 years. | 
| Phase II and III: Overall survival. | Overall survival is defined as the time from randomization until death from all causes combined. | Phase II: 5 years ; Phase III: 9 years. | 
| Phase II and III: Time to treatment failure. | Time to treatment failure is defined as the time from randomization to treatment discontinuation, whatever its cause. | Phase II: 5 years ; Phase III: 9 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial cancer, renal function impaired.