Title: A Randomised Multi-Stage Phase II/III Trial of Standard first-line therapy (sunitinib or pazopanib) Comparing Temporary Cessation with Allowing continuation, in the treatment of locally advanced and/or metastatic Renal Cancer (the STAR trial)
Funder: Department of Health and Social Care

Abstract: Sunitinib (trade name Sutent) and pazopanib (trade name Votrient) are drugs which target the blood supply of tumours and in recent years have become standard first-line treatment for patients with metastatic and/or locally advanced kidney cancer. Sunitinib/pazopanib treatment achieves increased survival, but is associated with significant toxicity. The STAR trial is a randomised controlled trial comparing the standard schedule of sunitinib or pazopanib (given in continuous cycles) to a modified schedule in which sunitinib or pazopanib cycles are given with planned treatment breaks (drug free intervals), tailored to the responses observed by tumour imaging in individual participants. The STAR trial aims to determine if the modified schedule of sunitinib or pazopanib is as effective as the standard schedule in terms of overall survival, whilst yielding benefits to participants in terms of reduced toxicity and improved quality of life, and to the NHS in terms of better cost effectiveness. The primary outcomes to the trial are overall survival and averaged Quality of Life Adjusted Years (QALYs). A QALY is a way of measuring both the quality and the quantity of life gained by a treatment. The initial stages of the trial aimed to recruit 210 patients from 16 NHS study sites to determine whether recruitment is feasible and the modified schedule of sunitinib looks to be effective. These targets were met in the summer of 2014 and the trial is now expanding to around 60 centres. In total 1000 patients will be recruited over a period of 65 months. At trial entry participants will be randomised equally to either receive sunitinib or pazopanib via the standard schedule of cycles every 6 weeks until progression, or to have the modified schedule with planned treatment breaks. Participants will have clinical assessment 6 weekly and CT/MRI scans 12 weekly until there is evidence of significantly worsening disease whilst receiving sunitinib or pazopanib.

Lay abstract: BACKGROUND Renal cancer is the 8th commonest cause of cancer-related deaths in the UK, with 10,144 new cases each year and 4,252 deaths (figures from 2012). Disease which is detected early may be operable and curable, but once the cancer has become advanced locally or has metastasised (spread to other organs), it is considered incurable. Previously, the commonly used drug therapy in the treatment of advanced/metastatic renal cell carcinoma, the commonest form of renal cancer, was interferon, but the proportion of tumours which responded was low and there was only minimal survival benefit. However, in a large trial, sunitinib, one of a new class of drugs which target the blood supply of tumours, was shown to be more effective than interferon in both response rate and survival and was approved by the National Institute for Health and Clinical Excellence (NICE) in February 2009. Pazopanib was also approved for first-line treatment by NICE in 2011. In current standard practice, sunitinib or pazopanib are given in continuous cycles, until disease progression or intolerability. Sunitinib is taken daily for 4 weeks out of a 6-week cycle; pazopanib is taken every day of the cycle. However, sunitinib and pazopanib have associated toxicities (fatigue, sore mouth, diarrhoea, high blood pressure, hand-foot syndrome and sickness) causing more than 40% of patients to discontinue treatment or require smaller doses. Also these drugs are expensive (for example, cost per 6-week cycle of sunitinib, around £3,700, with average total cost per patient around £47,000), with total NHS costs in England of the order of £75M for around 1600 patients. Estimates from our simulation show a likely reduction of approximately 21% in duration of treatment with a DFIS. This would correspond to a saving of around £10,000 per patient, which when extrapolated to annual NHS costs in England produces a simulated annual saving of approximately £16 million. If the survival benefit of sunitinib or pazopanib is maintained when it is given with planned treatment ‘holidays’ (i.e. using a drug-free interval strategy, DFIS, stopping treatment after patients have been on sunitinib or pazopanib for 6 months and restarting when disease progression occurs), rather than continuously as is current practice, there may be much-improved quality of life due to reduced toxicity, for patients, as well as releasing NHS resources. A strong rationale, including evidence from studies in other cancers underpins this hypothesis, but it has never been tested clinically and this is the purpose of the proposed study. DESIGN STAR is a 3-stage, phase II/III study of 1000 patients in around 60 NHS hospitals in which patients receiving sunitinib or pazopanib will be randomised equally to either the Conventional Continuation Strategy (CCS) arm or the DFIS arm. We have checked that the trial was recruiting sufficiently quickly (stage 1) and that time to strategy failure was not unacceptably shorter in the DFIS arm (stage 2) and have now progressed to the full phase III element of the trial (stage3). All patients will contribute to phase III, in which we will analyse outcomes to determine whether the survival benefit of sunitinib or pazopanib can be maintained with the DFIS approach, potentially with significantly improved patient quality of life and NHS value for money. We will also use a novel endpoint using QALYs (Quality Adjusted Life Years, which combines survival and quality of life in a single endpoint) which could be an exemplar for much wider application in future NIHR funded trials. ETHICAL ISSUES The study will require patients to give informed consent to be randomised to either arm, i.e. there is a 50% chance that they will enter the DFIS arm. It is particularly important that patients should fully understand the potential benefits and risks of randomisation to this arm, versus the standard continuous therapy that they would routinely receive. Such understanding is also vital for ensuring appropriate recruitment to the study. There is experience from intermittent drug studies in trials of other cancers on which we have drawn, but we have enhanced the usual Patient Information Leaflet with standardised audiovisual support media. In addition we carried out research using semi-structured interviews and a questionnaire in the phase II element of the trial into why patients consent or do not consent to the study with the aim to improve patient understanding/consent rates in the remainder of the study. EXPERTISE Our multidisciplinary study team is unique in the UK in having the range of expertise necessary to carry out the proposed clinical research in renal cancer and has vast experience in managing complex and challenging clinical studies. Team members have impressive international research standing, encompassing renal cancer clinicians, experts in statistical methodology, QoL assessment, health economics, patient and public awareness, health service and health psychology, strongly supported by the Leeds Clinical Trials Research Unit, which is among the foremost in the UK for management of complex clinical trials. One of our members (Peter Selby) is Joint-Director of the NIHR National Clinical Research Network and together and individually the team have responsibility for managing health-related grants measured in tens of millions of pounds.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS