Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma

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

Detailed Description
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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.

Official Title
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Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma

Conditions
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Malignant Pleural Mesothelioma

Intervention / Treatment
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* Radiation: Proton beam therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Control arm (standard of care) vs experimental arm (proton beam therapy) in 1:1 randomisation
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of care<br>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). | |
| Experimental: Proton beam therapy<br>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). | Radiation: Proton beam therapy<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Defined as the time from randomisation to the date of disease progression | From randomisation up to 2 years of follow up | 
| Overall survival | defined as the time from randomisation to the date of death from any cause. | From randomisation up to 2 years of follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of PBT-related adverse events as assessed by CTCAE v5.0 | AEs related to proton beam therapy will be collected | From start of PBT up to 2 years of follow up, for long term effects | 
| The EORTC quality of life questionnaire (QLQ), EORTC QLQ-C30 score, scale of 0-100. | 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. | From randomisation up to 2 years of follow up | 
| ED-5D-5L score | 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. | From randomisation up to 2 years of follow up | 
| 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. | From randomisation up to 2 years of follow up | 
| 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. | From randomisation up to 2 years of follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Proton beam therapy