Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma

Study design: Randomised phase III clinical trial for patients with unilateral MPM.Primary endpoint: Progression free survival (PFS) and overall survival (OS), defined asthe time from randomisation to the date of progression and death from any cause.Secondary Endpoints: Safety and Tolerability, Health related Quality of Life (QOL):EuroQoL EQ‐5D‐3L, Locoregional Control.Randomisation and stratification: 1:1 randomisation. Patients with be stratified forhistology (epithelioid versus non‐epithelioid), potential PBT centre (UCLH or TheChristie), laterality (left or right sided) and time since diagnosis (<1 year or > 1 year)Treatment:Experimental Arm: Patients in the experimental arm will receive PBT to the hemithorax toa dose of 50Gy in 25 fractions with a boost to 60Gy for the visible tumour (gross tumourvolume‐GTV). Treatment is given daily Monday‐Friday over 5 weeks. Following completion oftreatment in the experimental arm patients will have 2 years of follow‐up from time ofrandomisation at the local recruiting/referring centre.Control Arm:The patients in the control arm would be under standard of care surveillance i.e. "watchand wait", with no treatment or other intervention. Patients will have 2 years offollow‐up from time of randomisation at the local recruiting/referring centre. If thedisease progresses, the patient will receive SOC treatment i.e. immunotherapy withnivolumab and ipilimumab, or chemotherapy at the clinician's discretion.Statistical analysis plan:The sample size is 148 patients (74 patients per arm). This is to detect a OS hazardratio of 0.58, equivalent to an improvement in 2‐year OS from 30% to 50%, with 85% powerand 5% two‐sided alpha. Recruitment to complete in 3 years across 20 UK centres with 2years of additional follow‐up and up to 5% dropout. Interim analyses for OS efficacy willbe performed when 50, 75 and 110 patients have been randomised at around 1.5, 2.0 and 2.5years respectively. Using a fixed‐sequence approach, a difference for OS will only betested if the co‐primary endpoint of PFS is statistically significant (p<0.05); N=148will provide >85% power to detect a PFS hazard ratio of 0.58 accounting for up to 10%dropout.