A Phase III randomised trial of Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer

INTERVENTION: Product Name: Gemcitabine Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: Gemcitabine CAS Number: 95058‐81‐4 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 38‐ Trade Name: Cisplatin Product Name: Cisplatin Pharmaceutical Form: Solution for infusion INN or Proposed INN: Cisplatin CAS Number: 15663‐27‐1 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐ Product Name: Carboplatin Pharmaceutical Form: Solution for infusion INN or Proposed INN: Carboplatin CAS Number: 41575‐94‐4 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Product Name: Gemcitabine Pharmaceutical Form: Solution for infusion INN or Proposed INN: Gemcitabine CAS Number: 95058814 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 38‐ CONDITION: Therapeutic area: Diseases [C] ‐ Cancer [C04] Upper urinary tract transitional cell carcinoma ; MedDRA version: 15.0 Level: PT Classification code 10044407 Term: Transitional cell cancer of the renal pelvis and ureter System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) PRIMARY OUTCOME: Main Objective: Does chemotherapy given around the time of surgery (peri‐operative) extend the amount of time for which participants remain free of recurrent disease? Primary end point(s): The primary outcome measure is disease‐free survival (DFS). The main time point of interest is three years after randomisation. DFS is defined as the time from randomisation to the first of:; • Death (any cause); • Metastases; • Any ureteral or renal bed recurrence (invasive or non‐muscle invasive); Secondary Objective: ‐ Does peri‐operative chemotherapy increase overall survival time?; ; ‐ Does peri‐operative chemotherapy extend the amount of time for which participants remain free of widespread (metastatic) disease?; ; ‐ Does peri‐operative chemotherapy reduce the occurence of second upper urinary tract or bladder carcinomas?; ; ‐ What are the side effects associated with peri‐operative chemotherapy?; ; ‐ How well do participants allocated to chemotherapy adhere to the treatment regimen?; ; ‐ How do peri‐operative chemotherapy and surveillance affect participants' quality of life?; ; ‐ What impact do the findings of an embedded qualitative research study into recruitment have on accrual rates and study setup at subsequent sites? Timepoint(s) of evaluation of this end point: The primary analysis of DFS will be event driven. The primary time‐point of interest is 3 years and the Independent Monitoring Committee will advise the Trial Management Group when the primary endpoint should be analysed. SECONDARY OUTCOME: Secondary end point(s): • Trial feasibility, defined by recruitment rate over first two years; • Overall survival, defined as the time from randomisation to death from any cause; • Recurrence/second primary in the bladder; • Contralateral second primary utTCC; • Acute toxicity (on‐treatment / up to 3 months post‐randomisation); • Late toxicity (6 months – 5 years); • Treatment compliance (in the chemotherapy arm); • Metastasis free survival; • Quality of life (QoL) as measured by the EORTC QLQ‐C30 and EQ5D modules. Domains of interest include Global health/QL, functioning domains and items relating to fatigue and side‐effects associated with Gem‐Cis/Gem‐Carbo.; Timepoint(s) of evaluation of this end point: Trial feasibility will be assessed continuously during the first two years of recruitment. Acute toxicity will be analysed after all patients have completed 6 months of follow up. All other secondary endpoints will be evaluated after the requirements for analysis of the primary endpoint have been met. INCLUSION CRITERIA: 1.Written informed consent 2.=18 years of age 3.Post radical nephroureterectomy for upper tract tumour with predominant TCC component ‐ squamoid differentiation or mixed TCC/SCC is permitted. 4.Histologically confirmed TCC staged pT2‐pT4 pN0‐3 M0 or pTany N1‐3 M0 (providing all grossly abnormal nodes are resected). Patients with microscopically positive margins on pathology may be entered (providing all grossly abnormal disease was resected). 5.Satisfactory haematological profile (ANC> 1.5 x 109/L, platelet count 100 x 10/L ) and liver function tests (bilirubin < 1.5 x ULN, AST and Alkaline phosphatase < 2.5 x ULN), Glomerular filtration rate = 30 mls/min. 6.Fit and willing to receive adjuvant chemotherapy with first cycle to be commenced within 90 days of radical nephro‐ureterectomy if allocated 7.WHO performance status 0‐1. 8.Available for long‐term follow‐up Are the trial subjects under 18? no Number of subjects for this age range