Intensified methotrexate, vinblastine, doxorubicin and cisplatin (I-MVAC) with or without panitumumab as first-line treatment of advanced urothelial carcinoma in patients without H-Ras nor K-Ras mutations. Randomised phase II study

INTERVENTION: Trade Name: LEDERTREXATE 1000 mg Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: not less then Concentration number: 30‐ Trade Name: VELBE 10 mg Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: VINBLASTINE CAS Number: 865214 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: not less then Concentration number: 3‐ Trade Name: CISPLATINE DAKOTA PHARM Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: CISPLATIN CAS Number: 15663271 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: not less then Concentration number: 70‐ Trade Name: DOXORUBICINE ACTAVIS Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: DOXORUBICIN CAS Number: 23214‐92‐8 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: not less then Concentration number: 30‐ Trade Name: VECTIBIX Pharmaceutical Form: Solution for infusion INN or Proposed INN: PANITUMUMAB CAS Number: 339177‐26‐3 Concentration unit: mg/kg milligram(s)/kilogram Concentration type: not less then Concentration number: 6‐ CONDITION: Advanced urothelial carcinoma in patients without H‐Ras nor K‐Ras mutations ; MedDRA version: 12.1 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder PRIMARY OUTCOME: Main Objective: Evaluation of efficacy in terms of progression‐free survival at 9 months of the combination of intensified methotrexate, vinblastine, doxorubicin and cisplatin (I‐MVAC) with or without panitumumab as first‐line treatment of advanced urothelial carcinoma in patients without H‐Ras nor K‐Ras mutations. Primary end point(s): The primary endpoint is the evaluation of efficacy, in terms of progression‐free survival at 9 months, of the combination I‐MVAC with or without panitumumab.; The criterion for progression will be evaluated as per RECIST criteria (version 1.1 in Appendix 6) for measurable lesions or by the development of at least 1 new lesions evidenced during bone; scintigraphy. Secondary Objective: ‐ To assess toxicity (CTC AE v4.0); ‐ To assess response rate (RR); ‐ To assess overall survival (OS); ‐ To assess time to progression (TTP); ‐ To study the correlation between response rate, time to progression, overall survival and biological; parameters. INCLUSION CRITERIA: 1. Primary tumour of the bladder or upper urinary tract 2. Histologically confirmed infiltrating urothelial carcinoma (epidermoid and/or glandular forms are accepted) 3. Patients without H‐Ras nor K‐Ras mutations 4. Advanced disease defined by a locally advanced stage (T4 and/or N+) ineligible for surgical resection, or a metastatic stage (M1) 5. Patients with at least 1 evaluable lesion as per RECIST criteria (version 1.1) 6. 18 = age = 75 years 7. General condition 0 or 1 as per the WHO scale 8. Absence of previous chemotherapy for advanced disease (chemotherapy with gemcitabine and platinum salt delivered as an adjuvant is accepted if this ended more than a year ago) 9. Haematological function: Haemoglobin > 11 g/dl, neutrophils = 1500/mm3, platelets = 100,000/mm3 10. Liver function: Grade* 0 ASAT and ALAT (< grade* 3 for liver metastases), grade* 0 alkaline phosphatases, normal bilirubin 11. Renal function: calculated (