Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma

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.

Eligibility Criteria:
Inclusion criteria:

* Patients ≥18 years of age, with histologically (biopsy) confirmed MPM
* N0 or N1 and M0 disease
* Written informed consent
* Patient and responsible clinician opt for active surveillance and deferral of systemic anti-cancer therapy until clinical or radiological progression
* WHO Performance Status 0-1
* Disease confined to one hemithorax based on CT assessment
* Adequate pulmonary function:

  * ≥ 40% predicted post-FEV1;
  * ≥ 40% predicted DLCO/TLCO
* Agreement to travel to either proton beam therapy centres (i.e. UCLH or The Christie) if randomised to arm 2
* Agreement to be followed up at a local HIT-Meso trial site

Exclusion criteria:

* Presence of metastatic or contralateral disease
* Prior thoracic radiotherapy, chemotherapy, immunotherapy for MPM
* Prior radical surgery for MPM (extrapleural pneumonectomy or extended pleurectomy decortication or pleurectomy decortication)
* Initial systemic therapy or surgery is required and the patient and responsible clinician do not opt for active surveillance
* Involvement of contralateral or supraclavicular lymph nodes
* T4 disease with clear invasion of the myocardium
* N2 and/or M1 disease
* Presence of new effusion that is not amenable to drainage
* WHO Performance Status ≥ 2
* Women who are pregnant or breast feeding
* History of other malignancy; Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of treated non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy.