RATIONALE: Drugs used in chemotherapy, such as cisplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Giving pemetrexed disodium and cisplatin before surgery may shrink the tumor so that it can be removed during surgery. Giving radiation therapy after surgery may kill any remaining tumor cells.

PURPOSE: Phase II trial to study the effectiveness of neoadjuvant pemetrexed disodium and cisplatin followed by extrapleural pneumonectomy and radiation therapy in treating patients who have stage I, stage II, or stage III pleural mesothelioma.

Condition	Treatment or Intervention	Phase
localized malignant mesothelioma	Drug: cisplatin  Drug: pemetrexed disodium  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: enzyme inhibitor therapy  Procedure: neoadjuvant therapy  Procedure: radiation therapy  Procedure: surgery	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the pathological complete response rate in patients with stage I, II, or III pleural mesothelioma treated with neoadjuvant pemetrexed disodium and cisplatin followed by extrapleural pneumonectomy and radiotherapy.

Secondary

• Determine the 1- and 2-year disease-free and median survival of patients treated with this regimen.
• Determine the clinical response rate by radiological assessment in patients treated with this regimen.
• Determine the quantitative and qualitative toxic effects of this regimen in these patients.
• Determine the pattern of relapse (local vs metastatic) in patients treated with this regimen.
• Determine the time to event efficacy variables (i.e., time to objective tumor response, time to treatment failure, time to progressive disease, and overall survival) in patients treated with this regimen.
• Correlate response to treatment with this regimen with levels of TS, DHFR, GARFT, FPGS, DPD, RFCI, alpha-FR, and ERCC1 in the mesothelioma tissue of these patients.

OUTLINE: This is an open-label, multicenter study.

• Preoperative chemotherapy: Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Extrapleural pneumonectomy: Patients undergo extrapleural pneumonectomy within 3-8 weeks after the last course of chemotherapy.
• Hemi-thoracic radiotherapy: Beginning 4-8 weeks after surgery, patients undergo radiotherapy to the chest once daily 5 days a week for 6 weeks. Patients are followed every 3 months for 2 years.

PROJECTED ACCRUAL: A total of 77 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed pleural mesothelioma
• Stage I, II, or III (T1-3, N0-2, M0)
• No cardiac involvement

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 3.0 times ULN
• AST and ALT no greater than 3.0 times ULN

Renal

• Creatinine clearance at least 45 mL/min

Cardiovascular

• See Disease Characteristics
• Cardiac function adequate by radionuclide stress test, exercise stress test to maximal exercise level, or stress echocardiogram

Pulmonary

• FEV_1 at least 2 L OR at least 35% of predicted postoperative (ppoFEV_1)
• DLCO greater than 35% of ppoFEV_1
• PCO_2 less than 50 on ABG

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• Able and willing to take folic acid, cyanocobalamin, or dexamethasone
• Willing to have cytoreduction by extrapleural pneumonectomy
• No active infection
• Suitable candidate for this study therapy
• No concurrent serious systemic disorder (e.g., active infection) that would compromise the patient's safety or ability to complete the study
• No other primary malignancy except carcinoma in situ of the cervix, adequately treated nonmelanoma skin cancer, low-grade (Gleason score no greater than 6) localized adenocarcinoma of the prostate, or other malignancy curatively treated within the past 2 years with no evidence of recurrence

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior immunotherapy or biologic therapy
• No prior intracavity immunomodulators (chemical pleurodesis allowed)
• No concurrent immunotherapy or biologic therapy
• No concurrent routine filgrastim (G-CSF)
• No concurrent stimulator of thrombopoiesis

Chemotherapy

• No prior systemic chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent anticancer hormonal therapy

Radiotherapy

• No prior radiotherapy
• No concurrent radiotherapy

Surgery

• No prior surgical resection of mesothelioma
• Prior chemical pleurodesis allowed
• No concurrent anticancer surgery

Other

• More than 30 days since prior drug not approved for any indication
• No prior intracavity cytotoxic drugs (chemical pleurodesis allowed)
• No prior participation in this study or any other study investigating pemetrexed disodium
• No other concurrent experimental medication (thymidine allowed)
• No other concurrent anticancer therapy
• No nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates 2 days before, the day of, or 2 days after study therapy
• No NSAIDs or salicylates with a long half-life (e.g., piroxicam or nabumetone) 5 days before, the day of, or 2 days after study therapy

Massachusetts
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting

Study chairs or principal investigators

Lee M. Krug, MD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers:  CDR0000339681; MSKCC-03078; LILLY-H3E-US-JMGA; NCT00072397
Record last reviewed:  October 2003
Last Updated:  December 6, 2004
Record first received:  November 4, 2003
ClinicalTrials.gov Identifier:  NCT00072397
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08