Efficacy of Combination of Trastuzumab to Gemcitabine - Platinum Advanced or Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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A multicenter, randomized, Phase 2 trial to study the effectiveness and feasibility of association of trastuzumab with combination chemotherapy in advanced or metastatic bladder cancer patients. Combining monoclonal antibody therapy with combination chemotherapy may improve treatment efficacy on tumours overexpressed HER 2.

Official Title
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Multicenter Randomized Phase 2 Trial of Gemcitabine - Platinum With or Without Trastuzumab in Advanced or Metastatic Urothelial Carcinoma With HER2 Overexpression

Conditions
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Recurrent Bladder Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder

Intervention / Treatment
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* Biological: Trastuzumab
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Transitional cell carcinoma of the urothelium or bladder histologically proven stage IV AJCC [locally advanced (T4b and / or N + M0) unresectable or metastatic (M1)] Tumor and / or metastasis overexpressing HER2 immunohistochemistry (IHC 3 +) or IHC 2 + and FISH +. Centralized analysis. Measurable disease with at least one lesion with a diameter> 2 cm for conventional methods (clinical examination, CT or MRI) or> 1 cm for the helical scanner. In case of single metastasis, metastatic disease should be histologically proven Age ≥ 18 years and ≤80 years Life expectancy> 3 months, Index performance status <2 according to ECOG PS, No prior chemotherapy other than adjuvant and / or neoadjuvant chemotherapy, without Herceptin ® and complete for more than 6 months (naive to any previous chemotherapy in the metastatic setting) No radiotherapy within 4 weeks prior to inclusion, Normal cardiac function as measured by ejection fraction (LVEF> 50%), Blood and liver satisfactory constants: Hematological criteria: - Neutrophils> 1.5 x 109 / L, - Chips> 100 x 109 / L - Hemoglobin> 10 g / dL, Liver function: - Alkaline phosphatase (unless bone metastases) <2 x N - Total bilirubin <1.5 x N - transaminases (AST, ALT) <1.5 x N, renal Constants: - Creatinine clearance > 30 ml / min (Cockcroft and Gault, cf. Annex XV protocol) - Patient's written consent after full information. Exclusion Criteria: Concurrent treatment with an experimental drug, participation in another clinical trial within <30 days Patients previously treated with Herceptin ®, or another treatment targeting growth factors EGF (eg Iressa ®, Tarceva ®) Existence of a severe pulmonary disease, liver or kidney is likely to be exacerbated by the treatment, Other medical conditions: congestive heart failure or angina pectoris even if medically controlled failure, history of myocardial infarction before entering the trial, hypertension or uncontrolled arrhythmias, significant valvular disease, Patient with dyspnoea at rest or requiring oxygen therapy or with respiratory failure, Presence of a severe infection requiring antibiotics, Presence of CNS metastases or meningeal History of another malignancy uncured or cured for less than 5 years (except basal cell carcinoma, papillary thyroid carcinoma in situ of the cervix treated) Pregnant or lactating or not using effective contraception Women, For Cisplatin only: carrying a serious neurological disease, current events devices> NCI grade 2 neuropathy, hearing loss, creatinine clearance <60 ml / min, the patient can not support a patient hydration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Arm A: Platinum + Gemcitabine<br>Gemcitabine = 1 000 mg/m2 Day1 and Day8 given every 21 days IV + If Creatinin Clearance > 60 ml/min : Cisplatin = Day 1: 70 mg/m² given every 21 days If Creatinin Clearance < 60 ml/min : Carboplatin = Day 1: AUC 5 given every 21 days | Drug: Gemcitabine<br>* Given IV, 1000 mg/m² BSA on Day 1 and Day 8 every 21 days<br>* Other names: gemcitabin hydrochloride;Drug: Carboplatin<br>* Given IV: AUC 5 on Day 1 every 21 days<br>* Other names: Paraplatin;Drug: Cisplatin<br>* Given IV, 70 mg/m² BSA on day 1 every 21 days<br>* Other names: Biocisplatinum;|
| Experimental: Arm B: Platinum+Gemcitabine+Trastuzumab<br>Trastuzumab: Charging dose = 8mg/kg on day 1; then 6mg/kg every 21 days given IV + Gemcitabine = 1 000 mg/m2 Day1 and Day8 given every 21 days IV + If Creatinin Clearance > 60 ml/min : Cisplatin = Day 1: 70 mg/m² given every 21 days If Creatinin Clearance < 60 ml/min : Carboplatin = Day 1: AUC 5 given every 21 days | Biological: Trastuzumab<br>* Bottles of 150 mg; Charging dose: 8mg/kg then 6mg/kg every 21 days given IV<br>* Other names: MOAB HER2;Drug: Gemcitabine<br>* Given IV, 1000 mg/m² BSA on Day 1 and Day 8 every 21 days<br>* Other names: gemcitabin hydrochloride;Drug: Carboplatin<br>* Given IV: AUC 5 on Day 1 every 21 days<br>* Other names: Paraplatin;Drug: Cisplatin<br>* Given IV, 70 mg/m² BSA on day 1 every 21 days<br>* Other names: Biocisplatinum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free survival |  | Participants will be followed from radomization until progression or death, up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | Objective Response Rate will be assessed during treatment period, every 3 cycles, up to 7 months | 
| Number of participants with adverse events as a measure of safety and tolerability | Toxicity will be classify according to NCI-CTC criteria Version 2.0. Cardiac toxicity will be assessed according to the NYHA (New York Heart Association) criteria. | Participants will be followed all along the study period, an expected average of 3 years | 
| Quality of life | Quality of Life will be assessed according to the EORTC QLQ-C30 Version 3 questionnaire | Quality of Life will be assessed during the study period, every 3 cycles (Arm A patients) or every 3 months (Arm B patients), up to 3 years | 
| Overall survival |  | Participants will be followed from randomization until death or lost of follow-up, up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab, Treatment, Urothelial carcinoma