‘TransRAMPART’ stands for Translational sub-study of the Renal Adjuvant MultPle Arm Randomised Trial. The main RAMPART trial is a phase III controlled clinical platform trial of adjuvant therapy in patients with resected primary renal cell carcinoma (RCC) with high or intermediate risk of relapse. TransRAMPART itself is a translational sub-study within RAMPART, designed to develop a bio-repository of baseline and longitudinal samples that will enable researchers to undertake novel molecular analyses to address key clinically relevant questions around optimal management of patients with initially localised renal cancer. 

 

Although active monitoring through regular clinical and radiological assessments remains the current global standard of post-nephrectomy care, 30% of patients will go on to develop incurable metastatic RCC (mRCC) – increasing to 75% in patients with high risk disease – and there is a need for targeted adjuvant therapy and more accurate identification of patients at high risk of recurrence. The main RAMPART trial is a UK academic-led, international Multi-Arm Multi-Stage (MAMS) platform trial in intermediate and high risk localised RCC patients that randomises 1,175 participants between three trial arms: the current standard-of-care post-nephrectomy  (observation by clinical and radiological means), 1 year of the PD-L1 inhibitor durvalumab or a combination of 1 year of durvalumab and 2 cycles of the CTLA-4 inhibitor tremelimumab.  These are designed to evaluate multiple treatments simultaneously, while adapting to a changing landscape as data on different agents and combinations of agents emerges.   

 

As an academically-led trial, RAMPART provides a unique opportunity to evaluate a range of translational research angles prospectively linked with high-quality clinical trial data. TransRAMPART has therefore been designed as a translational sub-study that takes advantage of this opportunity by collecting tissue, blood and urine samples from patients already randomised to the RAMPART clinical trial, expanding the initial RAMPART sample collection to develop a TransRAMPART biorepository of baseline and longitudinal samples. Its primary aim is to develop and validate novel molecular signatures of prognosis, minimal residual disease, prediction of treatment response, resistance and toxicity in intermediate to high risk RCC patients within the RAMPART trial by assessing samples for potential immune, genomic, transcriptomic, proteomic and metabolomic biomarkers. The study also aims to describe the frequency and efficacy of any biomarkers for potential future therapeutic targets in RCC patients from medications given in RAMPART, and will feed into research on checkpoint inhibitors in mRCC with potential benefit to patients with advanced disease.  

 

Given the size of the RAMPART cohort and the comprehensive sampling of tumours involved, transRAMPART is uniquely positioned to identify biomarkers of response which could ultimately serve both adjuvant and metastatic RCC populations, as well as to identify recurrent mechanisms of resistance and immune-related adverse events. The results will guide development of optimal prognostic signatures, identification of RCC patients most in need of adjuvant checkpoint inhibitors, understanding of response and resistance to immunotherapy, and identification of patients most likely to experience significant toxicity.  Success in any of these would optimise treatment options and improve outcomes for patients with RCC.  

 

The planned target sample size for the initial three arms of the RAMPART trial is 1,175 patients, taking an estimated 5.5 years to full accrual, and it is expected that the majority of patients participating in the main RAMPART trial at UK sites will also participate in TransRAMPART. All patients who consent to take part in RAMPART agree to provide baseline FFPE tumour tissue and CPDA blood samples for genomic DNA.  Those who also consent to TransRAMPART will have additional blood, urine and tumour tissue samples taken alongside their RAMPART treatment and follow-up visits, either as part of TransRAMPART ‘Lite’ (blood and FFPE tissue) or TransRAMPART ‘Full’ (blood, FFPE tissue, fresh tissue and urine). 

 

The main co-primary outcome measures are disease-free survival (DFS) and overall survival (OS). DFS is defined as the interval from randomisation to first evidence of either local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first. OS is defined as the interval from randomisation to death from any cause (including RCC). Findings will be analysed and integrated within TransRAMPART as part of three interconnected working groups, each with their own set of hypotheses: Transcriptomics, proteomics and metabolics (led by Professor Grant Stewart), genomics (led by Dr Samra Turajlic) and immunology (led by Dr Sarah Welsh).  

 

Lead by Professor Grant Stewart as Chief Investigator, the TransRAMPART study is sponsored by UCL and co-ordinated by the MRC CTU at UCL in London. The study is funded through a Prospective Sample Collection Grant from Cancer Research UK (CRUK).