Advanced Urothelial Cancer, Metastatic Urothelial Cancer
Conditions
Keywords
Urothelial cancer, renal function impaired.
Brief summary
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.
Interventions
DRUGCarboplatin
Carboplatin AUC (area under curve) 4,5 at day 1 of each cycle until 6 cycles.
DRUGFractionated Cisplatin
Cisplatin 35mg/m² at day 1 and day 8 of each cycle until 6 cycles.
DRUGGemcitabine
Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.
Sponsors
Institut Claudius Regaud
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Efficacy - Rate of non progression at the end of treatment (C6D21). | 5 years. | Progression is defined according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria V1.1. |
| Phase III: Overall survival (in months). | 9 years. | Overall survival is defined as the time from randomization until death or last follow up news (censured data). |
| Phase II: Tolerance - Percentage of patients for whom at least one of the 3 defined tolerance criteria (see description) is observed. | 5 years. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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: Objective response. | Phase II: 5 years ; Phase III: 9 years. | Objective response (ie complete or partial response) will be evaluated according to RECIST v1.1 criteria. |
| Phase II and III: Overall survival. | Phase II: 5 years ; Phase III: 9 years. | Overall survival is defined as the time from randomization until death from all causes combined. |
| Phase II and III: Time to treatment failure. | Phase II: 5 years ; Phase III: 9 years. | Time to treatment failure is defined as the time from randomization to treatment discontinuation, whatever its cause. |
| Phase II and III: Progression free survival. | Phase II: 5 years ; phase III: 9 years. | Progression free survival will be evaluated according to RECIST v1.1 criteria. |
| 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. | Phase II: 5 years ; Phase III: 9 years. | 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). |
Countries
France
Outcome results
None listed