Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma (HIT-Meso)

Phase III randomised-controlled trial for patients with unilateral malignant pleural mesothelioma (MPM).

Study design: Randomised phase III clinical trial for patients with unilateral MPM. Primary endpoint: Progression free survival (PFS) and overall survival (OS), defined as the 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 for histology (epithelioid versus non-epithelioid), potential PBT centre (UCLH or The Christie) , 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 to a dose of 50Gy in 25 fractions with a boost to 60Gy for the visible tumour (gross tumour volume-GTV). Treatment is given daily Monday-Friday over 5 weeks. Following completion of treatment in the experimental arm patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. Control Arm: The patients in the control arm would be under standard of care surveillance i.e. "watch and wait", with no treatment or other intervention. Patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. If the disease progresses, the patient will receive SOC treatment i.e. immunotherapy with nivolumab 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 hazard ratio of 0.58, equivalent to an improvement in 2-year OS from 30% to 50%, with 85% power and 5% two-sided alpha. Recruitment to complete in 3 years across 20 UK centres with 2 years of additional follow-up and up to 5% dropout. Interim analyses for OS efficacy will be performed when 50, 75 and 110 patients have been randomised at around 1.5, 2.0 and 2.5 years respectively. Using a fixed-sequence approach, a difference for OS will only be tested if the co-primary endpoint of PFS is statistically significant (p<0.05); N=148 will provide >85% power to detect a PFS hazard ratio of 0.58 accounting for up to 10% dropout.

MPM participants who are on the standard of care watch and wait approach i.e. immediate treatment not suitable. Participants will have follow-up for 2 years (3 monthly in year 1, 4 monthly in year 2).

MPM participants to receive 5 weeks of proton beam therapy to the hemithorax. Following completion of treatment participants will have follow-up at the referring centre for 2 years (3 monthly in year 1, 4 monthly in year 2).

5 weeks (Mon-Fri) of proton beam treatment to the hemithorax to a dose of 50Gy in 25 fractions with a boost to 60Gy for the visible tumour (gross tumour volume-GTV).

Participant reported quality of life outcomes. The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / quality of life (QoL scale), and six single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Participant reported quality of life outcomes. The questionnaire comprises descriptive systems: mobility, self care, usual activities, pain/discomfort, anxiety/depression; scored from, level 1 to 5; level 1 indicating no problem and level 5 indicating unable to/extreme problems. There is also a scale from 0-100 to describe health status, 100 being the best health the patient can imagine, 0 being the worst health they can imagine.

Participant reported healthcare resource use from information collected on Client Service Receipt Inventory (CSRI)

A tool used to collect participant reported information on the range of healthcare services and supports study participants may use, to calculate the rate of service usage to evaluate resource use as part of health economic analysis.

Measurement of costs in economic evaluations using iMTA Valuation of Informal Care (iVICQ) questionnaire

Scoring (no scale) to evaluate health economics comparing PBT vs SOC surveillance and other SOC treatments for malignant pleural mesothelioma.

Inclusion Criteria: Histologically (Biopsy) confirmed malignant pleural mesothelioma No previous thoracic surgery T1N1, T2N0, T2N1, T3N0, T3N1 disease T4 and T4N1 disease if invasion of chest wall and ribs only WHO Performance Status 0-1 Age 18 years or over Pulmonary Function Tests: 40% predicted post-FEV1; 40% predicted DLCO (corrected for Hgb) Willing to travel to a proton beam therapy centre for treatment (if randomised to experimental arm) Exclusion Criteria: Presence of metastatic or contralateral disease, prior thoracic radiotherapy, prior radical surgery for MPM Nephrectomy on contralateral side Presence of new effusion that is not amenable to drain T1N0 disease T4 disease with invasion to heart and diaphragm M1 disease WHO Performance Status ≥ 2 Severe, active co-morbidity Women who are pregnant or breast feeding