Testing the Addition of Targeted Radiation Therapy to Surgery and the Usual Chemotherapy Treatment (Pemetrexed and Cisplatin [or Carboplatin]) for Stage I-IIIA Malignant Pleural Mesothelioma

PRIOR TO STEP 1 REGISTRATION - ALL PATIENTS

Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or biphasic malignant pleural mesothelioma (MPM)

Imaging proof of clinical stage (American Joint Committee on Cancer \[AJCC\] 8th edition) I-IIIA MPM by PET/CT;

* Diagnostic volumetric CT scan of the chest is preferred; however, the CT portion of the PET/CT may be used if CT imaging is of diagnostic quality

MPM is amenable to resection by P/D as determined by a thoracic surgeon

History/physical examination within 42 days prior to Step 1 Registration

Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 within 42 days prior to Step 1 Registration

Required Initial Laboratory Values prior to study entry (must be at least 14 days after last infusion of pre-study entry neoadjuvant therapy, if given):

* Absolute neutrophil count ≥1500 cells/mm3;

* Platelets ≥100,000 cells/mm3;

* Hemoglobin ≥ 8.0 g/dL;

* Serum total bilirubin ≤ 1.5 X ULN (upper limit of normal);

* Aspartate transferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine transaminase (ALT) (serum glutamic-oxaloacetic transaminase (SGPT)) ≤ 3.0 X ULN;

* Creatinine clearance ≥45 mL/min by the Cockcroft-Gault (C-G) equation

Negative serum pregnancy test within 14 days of Step 1 Registration for women of childbearing potential

HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility for this protocol.

The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

PRIOR TO STEP 1 REGISRATION - PATIENTS WHO RECEIVED SYSTEMIC THERAPY BEFORE STUDY ENTRY

The following systemic therapy and immunotherapy combinations are permissible: 1) cisplatin/carboplatin + pemetrexed; 2) cisplatin/carboplatin + pemetrexed + anti-PD-1/L1 agents; and 3) ipilimumab/nivolumab.

Patients must have received at least 2 cycles of neoadjuvant systemic therapy

PRIOR TO STEP 2 RANDOMIZATION - ALL PATIENTS

No evidence of progression as defined by PET/CT within 30 days prior to Step 2 randomization.

Patients must have received at least 2 cycles of systemic therapy and undergone a pleurectomy/decortication with the goal of macroscopic complete resection;

ECOG Performance Status 0-1 within 30 days prior to Step 2 Randomization

History/physical examination within 30 days prior to Step 2 Randomization

* • Active lung infection requiring IV antibiotics

* Patients on immunosuppressive therapy, for example history of organ or bone marrow transplant or other hematologic disorders that are expected to compromise life expectancy or tolerance of treatment;

Prior nephrectomy on the contralateral side of MPM

Ipsilateral thoracic electronic implant, e.g. pacemaker, defibrillator, unless switched to the contralateral side prior to initiation of radiation therapy (RT)

Prior thoracic radiation therapy (patients with prior thoracic RT cannot be planned to 50-60 Gy without exceeding normal tissue constraints)

Use of bevacizumab or other antiangiogenic therapy to treat current mesothelioma (due to potential for increased complications from local therapy).

For patients who received neoadjuvant systemic therapy prior to study entry, surgery planned to occur greater than 8 weeks following neoadjuvant systemic therapy

PRIOR TO STEP 2 RANDOMIZATION - ALL PATIENTS

Supplemental oxygen use

Third space fluid that cannot be controlled by drainage or insufficient lung expansion after P/D (this prevents targeting the pleura without exceeding normal tissue constraints)

Prior intrapleural therapy (i.e. intrapleural chemotherapy, photodynamic therapy); pleurodesis is permitted

Bulky residual disease in the major fissure preventing pleural IMRT

Patients who have undergone extrapleural pneumonectomy

Patients with active infection that requires systemic I.V. antibiotics, antiviral, or antifungal treatments

What this study is about