Clinical Trials in Renal Cancer.

Lead Research Organisation: University College London

Abstract

The renal team at the MRC CTU have experience in developing and co-ordinating multi-centre, randomised controlled clinical trials. Our previous trials have been in advanced kidney cancer (RE01, RE04) but we have now broadened our portfolio and developed a trial (RE05/SORCE) in early kidney cancer, i.e. cancer that is detected before it has had a chance to spread to other organs (metastasized). By doing so we hope to have a greater impact on the likelihood of a patient surviving the disease.||RE04 is a randomised, controlled phase III clinical trial that compared a proposed new combination treatment strategy in patients with advanced kidney cancer. When the trial started patients routinely received treatment with drugs that influence the workings of the immune system (immunotherapy). Interferon-alpha was the standard such drug used in the UK. In RE04 this standard was tested against a triple combination of interferon-alpha, interleukin-2 and 5-fluorouracil. The last-named drug is a so-called cytotoxic agent, which is a drug which kills cancer cells. The main aims of the trial are to evaluate the triple combination therapy compared with interferon-alpha alone in terms of how long the patients survive, how long they survive without progression of their cancer, the toxic effects of the therapies and patients quality of life. The results show that patients who received triple combination treatment did not live any longer than those who received interferon-alpha alone. It was also found that there was no difference in the length of time for the cancer to progress in the two groups of patients. The combination treatment was more toxic and had more unwanted side-effects.||RE05 (SORCE) is a trial in early stage kidney cancer. The standard treatment for patients with early or primary RCC is total or partial nephrectomy (surgical removal of the kidney). However, approximately in 30-50% of patients the disease spreads after initial nephrectomy with an intent to cure the patient. The new drug sorafenib has been shown to be active in advanced kidney cancer. It is hoped that by using sorafenib in early kidney cancer, the chance of a patients cancer returning or spreading will be reduced, thereby improving their survival prospects. RE05 is a randomised, double-blind placebo-controlled trial and has been designed to answer two questions. The first question is whether the drug sorafenib improves disease-free survival compared to placebo and the second question asks about the benefits of one year versus 3 years of treatment with sorafenib.

Technical Summary

Kidney or renal cell cancer (RCC) is the 13th commonest cancer diagnosed in the UK. The annual incidence in the UK is approximately 6,200 and rising, with around 2,500 deaths (CRUK figures 2006). Nearly 2 out 3 people diagnosed (62%) are over 65 years old. RCC is more common in men than in women. Approximately 25% of patients have metastatic disease at presentation. The renal team at the MRC CTU currently has 2 active trials in their portfolio. The RE04 trial in advanced RCC patients is closed to accrual but still in active follow-up, while the RE05 (SORCE) trial in the adjuvant treatment setting opened to accrual in July 2007. The standard therapy in the UK for patients with metastatic RCC was, until the recent introduction of targeted agents, single agent interferon-alpha (IFN-alpha) in those fit to tolerate treatment. RE04 is an open-label randomised controlled phase III trial to compare triple combination (IFN-alpha, IL-2 and 5FU) to monotherapy with IFN-alpha in this group of patients. The trial objectives were to assess (i) the value of the triple combination therapy in terms of overall survival time, progression-free survival time and toxicity compared with IFN-alpha alone (ii) the quality of life in patients in both treatment arms during therapy and follow-up and (iii) the health economic implications of using triple therapy compared to the control regimen. The trial closed to accrual in July 2006 having reached its accrual target of 1000 patients (1006 patients were recruited). Preliminary results have been published in abstract and presented in poster form at ASCO 2008. A paper presenting the results has been submitted to a leading medical journal and should be published later in 2009. RE05 (SORCE) is a multi-centre randomised phase III double-blind placebo-controlled study examining the efficacy and tolerability of sorafenib (Nexavar) in patients with resected (total or partial) primary RCC at high or intermediate risk or relapse. Sorafenib, an oral inhibitor of several kinases known to be important in the pathobiology of RCC, has been shown to prolong progression-free survival in advanced RCC and therefore a trial in the adjuvant setting is felt to be both timely and worthwhile. The trial aims to answer two questions. The first question is whether at least one year of treatment with sorafenib increases DFS (disease-free survival) compared with placebo. The second question is about the duration of sorafenib and whether three years of treatment increases DFS compared to one year of treatment. The trial opened in the UK in July 2007 and has a target accrual of 1656 patients over the next 5 years. The first international patient was recruited in February 2009. The countries that are taking part are Belgium, Holland and Italy (through the EORTC), Denmark, France, Spain, Australia and New Zealand. Two ancillary studies are currently taking place in the UK; a translational research programme (TRANSORCE) and a cost-effectiveness study. The translational research programme involves the collection of blood and/or fixed and fresh-frozen tumour (where available) from consenting patients and involves collaborations with the University of Leeds and the Institute of Cancer Research (UK). The cost-effectiveness study involves collaboration with the University of York.

Publications

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Blinman PL (2018) Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile? in Annals of oncology : official journal of the European Society for Medical Oncology

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Eisen T (2020) Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Henrion M (2013) Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer. in Human molecular genetics

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Henrion M (2013) Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer in Human Molecular Genetics

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Kramar A (2015) Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†. in Annals of oncology : official journal of the European Society for Medical Oncology

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Parmar MK (2014) More multiarm randomised trials of superiority are needed. in Lancet (London, England)

 
Description AstraZeneca support for start-up of RAMPART renal cancer adjuvant trial
Amount £694,715 (FKP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 03/2016 
End 12/2017
 
Description Collaboration on the RAMPART Clinical Trial - Adjuvant Kidney Cancer
Amount $22,000,000 (USD)
Organisation AstraZeneca 
Department Astra Zeneca
Sector Private
Country United States
Start 05/2018 
End 06/2029
 
Description Kidney Cancer UK - Support for RAMPART clinical trial
Amount £12,000 (GBP)
Organisation Kidney Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2017 
 
Description RAMPART Clinical Trial - Collaboration with AZ
Amount $22,000,000 (USD)
Organisation AstraZeneca 
Department Astra Zeneca
Sector Private
Country United States
Start 05/2018 
End 12/2029
 
Title TRANSORCE bank 
Description blood and tumour tissue from SORCE patients, to be associated with clinical ata 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact Identification of a gene associated with risk of developing renal cancer 
 
Description AstraZeneca start-up funding toward RAMPART international renal cancer adjuvant trial 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution An international consortium of key investigators in this field and a novel trial design
Collaborator Contribution Provision of start-up funds and drug information in support of the planned trial (which will itself have further funding)
Impact Development of trial underway and in discussion with regulatory authorities
Start Year 2016
 
Description Bayer support 
Organisation Bayer
Country Germany 
Sector Private 
PI Contribution The SORCE renal cancer adjuvant trial is a full collaboration between the MRC CTU and Bayer Pharmaceuticals (who supply agent, placebo, logistical support and partial funding). The CTU manages all aspects oof the trial and has alo set up a specimen bank that will provide a valuable resource for translational research in renal cancers and antiangiogenesis therapy.
Collaborator Contribution supply of drug, placebo and logistic support for international participantsProviding GWAS data to be associated with the clinical data
Impact Specimen bank (TRANSORCE) established
Start Year 2006
 
Description Bayer support 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution The SORCE renal cancer adjuvant trial is a full collaboration between the MRC CTU and Bayer Pharmaceuticals (who supply agent, placebo, logistical support and partial funding). The CTU manages all aspects oof the trial and has alo set up a specimen bank that will provide a valuable resource for translational research in renal cancers and antiangiogenesis therapy.
Collaborator Contribution supply of drug, placebo and logistic support for international participantsProviding GWAS data to be associated with the clinical data
Impact Specimen bank (TRANSORCE) established
Start Year 2006
 
Description ICR work on GWAS 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution We established the bank and ICR will provide the GWAS data, potentially valuable in addressing a number of clinical questions
Collaborator Contribution Performing Genome Wide Association studies on SORCE specimens (TRANSORCE)
Impact Identification of a gene (ZEB2) associated with increased risk of development of renal cancer, currently in press in Human Molecular Genetics
Start Year 2011
 
Description UCL - Astra Zeneca: RAMPART Trial - Main Collaboration Agreement 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution MRC CTU at UCL has led on the design of this trial, is leading on all aspects of trial conduct and will lead on all aspects of trial analysis, reporting and the dissemination of results.
Collaborator Contribution Astra Zeneca have agreed to provide USD$22,000,000 to support the cost of the trial. They are also providing free trial drugs to sites (including cost of distribution).
Impact No outputs to date.
Start Year 2018
 
Description UCL - Kidney Cancer UK - RAMPART Trial 
Organisation Kidney Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution MRC CTU at UCL has led on the design of the RAMPART trial, is leading on all aspects of trial conduct and will lead on all aspects of trial analysis, reporting and the dissemination of results.
Collaborator Contribution Kidney Cancer UK peer-reviewed and approved the RAMPART trial, consequently the trial was adopted onto the NCRI trials portfolio. Kidney Cancer UK have agreed to provide funding to support patient-centred activities.
Impact No outcomes to date
Start Year 2018