| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Upper urinary tract transitional cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| This cancer affects the cells which line the inside of the kidney (renal pelvis) and the ureter which connects the kidney to the bladder. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10044407 |
| E.1.2 | Term | Transitional cell cancer of the renal pelvis and ureter |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Does chemotherapy given around the time of surgery (peri-operative) extend the amount of time for which participants remain free of recurrent disease? |
|
| E.2.2 | Secondary objectives of the trial |
- 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? |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 4 sub-studies within POUT:
QUALITY OF LIFE
The main objective of this study is to establish how peri-operative chemotherapy and surveillance affect participants' quality of life.
QUALITATIVE RECRUITMENT SUB-STUDY (QRS)
The aim of the QRS in the POUT feasibility study is to work with RCT staff to understand the recruitment process in the early stages, so that any design or conduct problems can be raised and changes put in place. It will also be used to determine any staff training that need to be developed or feedback given to staff.
POUT TRANSLATIONAL STUDY
Consent for access to paraffin blocks from nephro-ureterectomy will be sought to allow collection of tissue sections for analysis at a later date.
IMAGING BIOMARKERS STUDY
Participants will be asked at study entry for consent for access to pre-operative CT urograms. Images will be collected for a study to evaluate the prognostic value of pre-operative CT urograms. This retrospective review is intended to correlate imaging with pathological staging and may allow better prediction of subsequent muscle invasive pathology. |
|
| E.3 | Principal 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 |
|
| E.4 | Principal exclusion criteria |
1.Evidence of distant metastases
2.Pure adenocarcinoma, squamous cell carcinoma or small cell or other variant histology
3.Un-resected macroscopic nodal disease
4.Concurrent muscle invasive bladder cancer (patients with concurrent Non-muscle invasive bladder cancer (NMIBC) will be eligible)
5.GFR <30 mls/minute. NB Gemcitabine-carboplatin can only be given for patients with suboptimal renal function for cisplatin ie for GFR 30-49mls/min. Patients with poor performance status or co-morbidities that would make them unfit for chemotherapy are ineligible for the trial
6.Significant co-morbid conditions that would interfere with administration of protocol treatment
7.Pregnancy; lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception (male patients should also use contraception if sexually active);
8.Previous malignancy in the last 5 years except for previous NMIBC, adequately controlled non melanoma skin tumours, CIS of cervix or LCIS of breast or localised prostate cancer in patients who have a life expectancy of over 5 years upon trial entry. |
|
| E.5 End points |
| E.5.1 | 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)
|
|
| E.5.1.1 | 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. |
|
| E.5.2 | 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.
|
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Surveillance for signs of recurrence |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study end date is deemed to be the date of last data capture. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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