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

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

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.

Study Overview

• Status: Completed
• Conditions: Malignant Mesothelioma
• Intervention / Treatment: Drug: Cisplatin; Drug: Pemetrexed; Procedure: Therapeutic conventional surgery; Radiation: Radiotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Freiburg, Germany, D-79106
    • Universitaetsklinikum Freiburg
• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonsspital Aarau
  • Baden, Switzerland, CH-5404
    • Kantonsspital Baden
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Bern 4, Switzerland, 3004
    • Spital Tiefenau
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Lausanne, Switzerland, CH-1011
    • Centre hospitalier universitaire vaudois
  • Olten, Switzerland, CH-4600
    • Kantonsspital Olten
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • SpitalSTS AG Simmental-Thun-Saanenland
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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.

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Rolf A. Stahel, Prof, Universitaetsspital Zuerich

Publications and helpful links

General Publications

• Stahel RA, Riesterer O, Xyrafas A, Opitz I, Beyeler M, Ochsenbein A, Fruh M, Cathomas R, Nackaerts K, Peters S, Mamot C, Zippelius A, Mordasini C, Caspar CB, Eckhardt K, Schmid RA, Aebersold DM, Gautschi O, Nagel W, Topfer M, Krayenbuehl J, Ribi K, Ciernik IF, Weder W. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015 Dec;16(16):1651-8. doi: 10.1016/S1470-2045(15)00208-9. Epub 2015 Nov 2.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2005
• Primary Completion (Actual): March 26, 2014
• Study Completion (Actual): January 23, 2018

Study Registration Dates

• First Submitted: June 7, 2006
• First Submitted That Met QC Criteria: June 7, 2006
• First Posted (Estimate): June 8, 2006

Study Record Updates

• Last Update Posted (Actual): May 15, 2019
• Last Update Submitted That Met QC Criteria: May 13, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: sarcomatous mesothelioma; epithelial mesothelioma; stage II malignant mesothelioma; stage III malignant mesothelioma; stage IA malignant mesothelioma; stage IB malignant mesothelioma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Cisplatin; Pemetrexed
• Other Study ID Numbers: SAKK 17/04; SWS-SAKK-17/04; EU-20615; 2006-000445-19 (EudraCT Number); LILLY-SAKK-17/04 (Other Identifier: SAKK); CDR0000481153