Pemetrexed Disodium and Cisplatin Followed by Surgery With or Without Radiation Therapy in Treating Patients With Malignant Pleural Mesothelioma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This randomized phase II trial is studying how well giving pemetrexed disodium together with cisplatin followed by surgery with or without radiation therapy works in treating patients with malignant pleural mesothelioma.

Detailed Description
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OBJECTIVES: Primary Evaluate the short-term outcomes and feasibility of neoadjuvant therapy with pemetrexed disodium and cisplatin followed by extrapleural pneumonectomy in patients with malignant pleural mesothelioma. Evaluate the long-term outcomes and feasibility of postoperative hemithoracic radiotherapy in patients with R0 or R1 resection. Secondary Determine the quality of life of these patients. Identify predictive and prognostic markers in these patients. Determine relapse-free or progression-free survival and overall survival of these patients. Collect tissue and blood from these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, histology (sarcomatous or other vs epithelial or mixed histology), nodal status (N0-1 vs N2), and extent of disease (T1-2 vs T3). Part 1 (neoadjuvant therapy and surgery): Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Within 8 weeks after completion of neoadjuvant therapy, patients without progressive disease undergo extrapleural pneumonectomy. Part 2 : Patients achieving R0 or R1 resection proceed to part 2 of study treatment and are randomized to 1 of 2 treatment arms. Patients with R2 resection, disease progression, or symptomatic deterioration after treatment in part 1 are taken off study. Arm I (no postoperative radiotherapy): Patients do not undergo radiotherapy. Quality of life is assessed at baseline and at 6, 10, 16, and 22 weeks after randomization. Arm II (postoperative radiotherapy): Beginning within 10 weeks after surgery, patients undergo radiotherapy to the hemithoracic region 5 days a week for approximately 5 weeks in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and at 4, 8, 14, and 20 weeks after initiation of radiotherapy. Patients undergo blood and tissue collection at registration and surgery for laboratory and biomarker analysis. After completion of study treatment, patients are followed periodically for up to 5 years after surgery. PROJECTED ACCRUAL: A total of 155 patients will be accrued for this study.

Official Title
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Neoadjuvant Chemotherapy and Extrapleural Pneumonectomy of Malignant Pleural Mesothelioma (MPM) With or Without Hemithoracic Radiotherapy. A Randomized Multicenter Phase II Trial

Conditions
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Malignant Mesothelioma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Pemetrexed
* Procedure: Therapeutic conventional surgery
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed malignant pleural mesothelioma T1-3, N0-2, M0 disease according to International Mesothelioma Interest Group staging system No obvious invasion of mediastinal structures by CT scan (e.g., heart, aorta, spine, esophagus) No obvious widespread chest wall invasion Resectable chest wall lesions allowed PATIENT CHARACTERISTICS: WHO performance score 0-1 Fit for neoadjuvant therapy, surgery, and postoperative radiotherapy Creatinine clearance > 60 mL/min Hemoglobin ≥ 10.0 g/dL WBC ≥ 3,500/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 1.5 times ULN Alkaline phosphatase ≤ 1.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for up to 12 months after completion of study treatment FEV_1 ≥ 40% of predicted based on spirometry and lung perfusion scan, if necessary No serious underlying medical condition that would preclude study requirements (e.g., active autoimmune disease or uncontrolled diabetes) No known hypersensitivity against pemetrexed disodium, cisplatin, or other platinum-containing substances or any other components used for the preparation of the drugs No restricted power of hearing (especially in the upper frequency range) No acute infections PRIOR CONCURRENT THERAPY: No prior chemotherapy No treatment on another clinical trial within the past 30 days No prior pleurectomy or lung resection No prior radiotherapy of the lower neck, thorax, or upper abdomen No aspirin, cyclooxygenase-2 inhibitors, or nonsteroidal anti-inflammatory agents for 5 days prior to, during, and for 2 days after pemetrexed disodium administration No other concurrent experimental drugs or anticancer therapy No concurrent drugs that would contraindicate study drugs No concurrent vaccination against yellow fever

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: No radiotherapy<br> | Drug: Cisplatin<br>* Cisplatin 75 mg/m2 i.v. over approximately 2 hours on day 1 every 21 days<br>Drug: Pemetrexed<br>* Pemetrexed 500 mg/m2 i.v. over approximately 10 minutes on day 1 every 21 days<br>Procedure: Therapeutic conventional surgery<br>* Extrapleural pneumonectomy<br>|
| Experimental: Radiotherapy<br> | Drug: Cisplatin<br>* Cisplatin 75 mg/m2 i.v. over approximately 2 hours on day 1 every 21 days<br>Drug: Pemetrexed<br>* Pemetrexed 500 mg/m2 i.v. over approximately 10 minutes on day 1 every 21 days<br>Procedure: Therapeutic conventional surgery<br>* Extrapleural pneumonectomy<br>Radiation: Radiotherapy<br>* CTV1 will receive 45 or 46 Gy. CTV2 will be treated up to a total dose of 55,9 to 56,2 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete macroscopic resection (part 1) |  | After surgery (15 weeks after trial registration) | 
| Loco-regional relapse-free survival (part 2) |  | From surgery until the first occurrence of loco-regional relapse | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to neoadjuvant therapy (part 1) |  | Every 6 months in the follow-up until death for a maximum of 5 years | 
| Adverse drug reaction to neoadjuvant therapy (part 1) |  | According to CTCAE | 
| Operability (part 1) |  | Proportion of patients remaining operable after completing chemotherapy (9 weeks after trial registration) | 
| Surgical complications (part 1) |  | Within 3 month after surgery | 
| Reasons for non-randomization (part 1) |  | Reasons for non-randomization include macroscopic incomplete resection, patients' refusal or patient can not be subjected to RT within 10 weeks after surgery. | 
| Relapse-free or progression-free survival (part 1) |  | From registration until progression/relapse (loco-regional or distant) or death | 
| Adverse reaction to postoperative radiotherapy (part 2) |  | According to CTCAE | 
| Late toxicity (part 2) |  | Late toxicities occurring later than 6 weeks after the last RT fraction | 
| Feasibility of postoperative radiotherapy (part 2) |  | Proportion of patients receiving at least 90% of planned RT dose | 
| Relapse-free survival (part 2) |  | From registration until progression/relapse (loco-regional or distant) or death | 
| Psychological distress (quality of life) (part 2) |  | Until 22 weeks after treatment termination | 
| Overall survival |  | From registration until death for all registered patients, and from randomization to death for all randomized patients. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II malignant mesothelioma, epithelial mesothelioma, sarcomatous mesothelioma, stage IA malignant mesothelioma, stage IB malignant mesothelioma, stage III malignant mesothelioma