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

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Completed

CT.gov ID

NCT00334594

Collaborator

(none)

153

Enrollment

Locations

Arms

146.3

Actual Duration (Months)

11.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Mesothelioma	Drug: Cisplatin Drug: Pemetrexed Procedure: Therapeutic conventional surgery Radiation: Radiotherapy	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

153 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 14, 2005

Actual Primary Completion Date :

Mar 26, 2014

Actual Study Completion Date :

Jan 23, 2018

Arms and Interventions

Arm	Intervention/Treatment
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
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.

Arm

Intervention/Treatment

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

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.

Outcome Measures

Primary Outcome Measures

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

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.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 69 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
2	Kantonsspital Aarau	Aarau	Switzerland	CH-5001
3	Kantonsspital Baden	Baden	Switzerland	CH-5404
4	Universitaetsspital-Basel	Basel	Switzerland	CH-4031
5	Spital Tiefenau	Bern 4	Switzerland	3004
6	Inselspital Bern	Bern	Switzerland	CH-3010
7	Kantonsspital Bruderholz	Bruderholz	Switzerland	CH-4101
8	Kantonsspital Graubuenden	Chur	Switzerland	CH-7000
9	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011
10	Kantonsspital Olten	Olten	Switzerland	CH-4600
11	Kantonsspital - St. Gallen	St. Gallen	Switzerland	CH-9007
12	SpitalSTS AG Simmental-Thun-Saanenland	Thun	Switzerland	3600
13	UniversitaetsSpital Zuerich	Zurich	Switzerland	CH-8091