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

Study Overview
=================
Brief Summary
-----------------
This trial studies how well the addition of targeted radiation therapy to surgery and the usual chemotherapy treatment works for the treatment of stage I-IIIA malignant pleural mesothelioma. Targeted radiation therapy such as intensity-modulated radiation therapy or pencil beam scanning uses high energy rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving targeted radiation therapy in addition to surgery and chemotherapy may work better than surgery and chemotherapy alone for the treatment of malignant pleural mesothelioma.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To detect an improvement in overall survival with the addition of adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) to surgery and chemotherapy compared to surgery and chemotherapy alone. SECONDARY OBJECTIVES: I. To determine local failure-free survival, distant-metastases-free survival, and progression-free survival with the addition of adjuvant hemithoracic IMPRINT to surgery and chemotherapy compared to surgery and chemotherapy alone. II. To evaluate the treatment-related toxicities in both arms per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. III. To detect a clinically meaningful 10-point change in global health status mean scores at 9 months after randomization with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone. EXPLORATORY OBJECTIVES: I. To evaluate the degree of under-staging, concordant and upstaging between centrally-reviewed clinical staging (based on positron emission tomography [PET], computed tomography [CT] and/or magnetic resonance imaging [MRI]) and pathologic staging. II. To identify immunologic and pathologic biomarkers as predictors of response and potential targets for future combination trials. III. To determine the magnitude of radiation dose escalation to gross residual disease based on combined modality imaging and associated local control rates with dose-painting intensity-modulated radiation therapy (IMRT). IV. To determine the rate of R0/R1 and R2 resections, and type of procedures (extended pleurectomy/decortication [P/D], P/D and partial pleurectomy). V. To evaluate the trajectory of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-Q30) and lung cancer specific module (LC13) symptoms in patients treated with IMPRINT by comparing the proportion of patients who respond with quite a bit or very much LC13 symptoms at 9-12 months post-randomization compared to at 3 months post-randomization. VI. To evaluate changes in health-related quality of life, functional domains, and symptoms over time with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone. OUTLINE: STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed intravenously (IV) over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1. Patients may instead receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1 then undergo P/D within 4 to 8 weeks after chemotherapy. The order of surgery and chemotherapy is at the discretion of the treating physician. STEP 2: Within 4 to 8 weeks from the end of Step 1 treatment, patients are randomized to 1 of 2 arms. ARM I: Patients receive no treatment. ARM II: Patients undergo 25-28 fractions IMRT or pencil beam scanning (PBS) proton therapy 5 days per week over 6 weeks. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

Official Title
-----------------
Phase III Randomized Trial of Pleurectomy/Decortication Plus Systemic Therapy With or Without Adjuvant Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Malignant Pleural Mesothelioma (MPM)

Conditions
-----------------
Pleural Biphasic Mesothelioma, Pleural Epithelioid Mesothelioma, Stage I Pleural Malignant Mesothelioma AJCC v8, Stage IA Pleural Malignant Mesothelioma AJCC v8, Stage IB Pleural Malignant Mesothelioma AJCC v8, Stage II Pleural Malignant Mesothelioma AJCC v8, Stage IIIA Pleural Malignant Mesothelioma AJCC v8

Intervention / Treatment
-----------------
* Drug: Carboplatin
* Drug: Cisplatin
* Procedure: Decortication
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Pemetrexed
* Drug: Pemetrexed Disodium
* Radiation: Pencil Beam Scanning
* Procedure: Pleurectomy
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or biphasic malignant pleural mesothelioma (MPM) within 90 days prior to Step 1 Registration Imaging proof of clinical stage (American Joint Committee on Cancer [AJCC] 8th edition) I-IIIA MPM by PET/CT within 42 days prior to Step 1 Registration MPM is amenable to resection by P/D as determined by a thoracic surgeon within 42 days prior to Step 1 Registration History/physical examination within 42 days prior to Step 1 Registration Karnofsky performance status >= 80 within 42 days prior to Step 1 Registration Pulmonary function tests within 42 days prior to Step 1 Registration: >= 40% predicted post-forced expiratory volume in 1 second (FEV1); >= 40% predicted post-operative diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hgb]) Leukocytes >= 3000 cells/mm^3 (within 30 days prior to Step 1 Registration) Absolute neutrophil count >= 1500 cells/mm^3 (within 30 days prior to Step 1 Registration) Platelets >= 100,000 cells/mm^3 (within 30 days prior to Step 1 Registration) Serum total bilirubin =< 1.5 X upper limit of normal (ULN) (within 30 days prior to Step 1 Registration) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X ULN (within 30 days prior to Step 1 Registration) Glomerular filtration rate (GFR): >= 50 mL/min/1.73 m^2 (must be calculated using estimated creatinine clearance [CrCl] by the Cockcroft-Gault [C-G] equation [Nephron 1976;16:31-41]) (within 30 days prior to Step 1 Registration) Negative serum pregnancy test within 14 days of Step 1 Registration for pre-menopausal women of childbearing potential The patient or a legally authorized representative must provide study-specific informed consent prior to study entry EORTC QLQ-C30 and QLQ-LC13 within 42 days prior to Step 1 Registration PRIOR TO STEP 2 RANDOMIZATION INCLUSION CRITERIA Patients must have received at least 2 cycles of pemetrexed/platinum chemotherapy and undergone a pleurectomy/decortication with the goal of macroscopic complete resection following step 1 Registration Karnofsky performance status >= 70 within 30 days prior to Step 2 Randomization History/physical examination within 30 days prior to Step 2 Randomization EORTC QLQ-C30 and QLQ-LC13 within 30 days prior to Step 2 Randomization Exclusion Criteria: PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA Pregnant or lactating women, or sexually active men or women not using effective contraception (risk for fetal defects from teratogenic chemotherapy and radiation therapy) within 14 days prior to Step 1 Registration Diagnosis of sarcomatoid mesothelioma Severe, active co-morbidity defined as follows: New York Heart Association (NYHA) class III or IV heart failure Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are allowed; Unstable angina requiring hospitalization and/or transmural myocardial infarction within the last 3 months; Interstitial lung disease; Hemodialysis or peritoneal dialysis; Concurrent active malignancy (with the exception of current or prior non-melanomatous skin cancer or low-grade malignancies followed observantly for which treatment has not or does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen) If evidence of disease < 3 years, institution must consult with the principal investigator, Andreas Rimner, Doctor of Medicine (MD) Hepatic impairment defined by ChildPugh class (ChildPugh class B & C); For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within 30 days prior to registration, if indicated. Note: HBV viral testing is not required for eligibility for this protocol Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 30 days prior to registration Active tuberculosis Patients on immunosuppressive therapy, for example history of organ or bone marrow transplant or chronic lymphocytic leukemia (CLL); CD4 count < 200 cells/microliter. Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol 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) PRIOR TO STEP 2 RANDOMIZATION EXCLUSION CRITERIA Progressive disease 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Step 1: chemotherapy, P/D: Step 2: no treatment)<br>STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1. Patients may instead receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1 then undergo P/D within 4 to 8 weeks after chemotherapy. The order of surgery and chemotherapy is at the discretion of the treating physician. STEP 2: Patients receive no treatment. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Decortication<br>* Undergo decortication<br>Drug: Pemetrexed<br>* Given IV<br>* Other names: Multitargeted Antifolate;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Procedure: Pleurectomy<br>* Undergo pleurectomy<br>* Other names: Excision of Pleura;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (Step 1: chemotherapy, P/D, Step 2: IMRT/PBS)<br>STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1. Patients may instead receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1 then undergo P/D within 4 to 8 weeks after chemotherapy. The order of surgery and chemotherapy is at the discretion of the treating physician. STEP 2: Within 4-8 weeks from the end of Step 1 treatment, patients undergo 25-28 fractions IMRT or PBS proton therapy 5 days per week over 6 weeks. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Decortication<br>* Undergo decortication<br>Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Pemetrexed<br>* Given IV<br>* Other names: Multitargeted Antifolate;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Radiation: Pencil Beam Scanning<br>* Undergo PBS<br>Procedure: Pleurectomy<br>* Undergo pleurectomy<br>* Other names: Excision of Pleura;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will compare the distributions of OS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of OS for each arm will be estimated using the Kaplan-Meier method. The associated 90% confidence interval (CI) will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios will be estimated using a stratified Cox regression model. | From the date of randomization and the date of death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local-failure-free survival (LFFS) | Will compare the distributions of LFFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of LFFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for LFFS will be estimated using a stratified Cox regression model. | From randomization to local disease progression or death due to any cause, whichever occurs first, assessed up to 5 years | 
| Distant-metastases-free survival (DMFS) | Will compare the distributions of DMFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of DMFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for PFS will be estimated using a stratified Cox regression model. | From randomization to distant metastases or death due to any cause, whichever occurs first, assessed up to 5 years | 
| Progression-free survival (PFS) | Will compare the distributions of PFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for PFS will be estimated using a stratified Cox regression model. | From randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 5 years | 
| Incidence of treatment-related toxicity | Adverse events (AEs) will be graded with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All adverse events, adverse events leading to withdrawal, interruption or modification of protocol treatment, grade >= 3 adverse events, and serious adverse events will be summarized. Deaths and cause of death will be summarized. The rate of treatment-related adverse events will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm. | Up to 5 years | 
| Quality of Life (QOL)/patient-reported Outcome (PRO) | Measured by European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires. | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mesothelioma, IMPRINT