Pemetrexed Plus Gemcitabine or Carboplatin for Patients With Advanced Malignant Pleural Mesothelioma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as pemetrexed disodium, gemcitabine, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether giving pemetrexed disodium with gemcitabine is more effective than giving pemetrexed disodium with carboplatin in treating malignant pleural mesothelioma. PURPOSE: This randomized phase II trial is studying pemetrexed disodium with gemcitabine and pemetrexed disodium with carboplatin to see how well the combinations work compared to historical controls in treating patients with advanced malignant pleural mesothelioma.

Detailed Description
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OBJECTIVES: Primary Estimate the response rates in patients with advanced malignant mesothelioma of the pleura treated with pemetrexed disodium combined with either gemcitabine or carboplatin. Secondary Assess the toxic effects of these regimens in these patients. Estimate survival time in patients treated with these regimens. Correlate smoking status with outcome in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. While randomized, the study is not a comparative study. Rather, outcomes on each arm will be compared to a historical control rate from previous studies. Randomization allows simultaneous testing of two experimental arms. Arm I: Patients receive intravenous (IV) pemetrexed disodium over 10 minutes and carboplatin IV over 30 minutes on day 1. Arm II: Patients receive pemetrexed disodium as in arm I and gemcitabine IV over 30 minutes on days 1 and 8. In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning approximately 5-10 days before the start of chemotherapy and continuing until approximately 3 weeks after completion of chemotherapy, all patients receive oral folic acid once daily and cyanocobalamin (vitamin B12) intramuscularly every 9 weeks. Patients are followed every 3 months for 2 years and then every 6 months for 1 year. PROJECTED ACCRUAL: A total of 32-60 patients (16-30 per treatment arm) will be accrued for this study within 12.8-27.0 months.

Official Title
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Pemetrexed Plus Gemcitabine Or Carboplatin In Patients With Advanced Malignant Mesothelioma: A Randomized Phase II Trial

Conditions
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Mesothelioma

Intervention / Treatment
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* Drug: pemetrexed disodium
* Drug: gemcitabine hydrochloride
* Drug: carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced mesothelioma of the pleura Measurable disease, as defined by RECIST criteria, within 4 weeks of randomization. Patients with pleural rinds not measurable by RECIST were eligible if disease was evaluable within 4 weeks of randomization using mesothelioma response criteria May have undergone pleurodesis. If pleurodesis was performed, there must have been at least a 2-week delay before Pemetrexed administration. A CT must have been performed after 2 weeks after pleurodesis to serve as the baseline scan. ECOG Performance Status of 0 or 1 Normal organ and marrow function, as defined by: Absolute neutrophil count ≥ 1,500/ul Platelet count ≥ 100,000/ul Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement) Albumin ≥ 2.5 g/dL Creatinine clearance ≥ 45 mL/min or Creatinine ≤ 2.0 g/dL Age 18 years and over Able to take folic acid and cyanocobalamin (vitamin B12) Willing and able to take dexamethasone Women of childbearing potential and sexually active men were required to use contraception during and for the first 3 months after the study Exclusion Criteria A candidate for curative surgery Prior radiation therapy to the target lesion, unless the lesion was clearly progressing per RECIST criteria after prior radiation and the interval between the most recent radiation therapy and enrollment was at least 4 weeks Prior systemic chemotherapy for mesothelioma. Prior intracavitary cytotoxic drugs or immunomodulators were not permitted, unless given for the purpose of pleurodesis. Active infection or serious concomitant systemic disorder Second primary malignancy, other than in situ malignancies or adequately treated basal cell carcinoma of the skin or other malignancy treated at least 3 years previously with no evidence of recurrence. Treatment with an investigational agent within 4 weeks before enrollment Known or suspected brain metastases Women must not be pregnant or breastfeeding Obviously malnourished or with a weight loss of greater than 10% in the preceding 6 weeks Aspirin or other nonsteroidal anti-inflammatory drugs for 2 days before, during, and for 2 days after each administration of pemetrexed disodium (5 days before, during, and 2 days after each administration of pemetrexed disodium for piroxicam, naproxen, diflunisal, or nabumetone)

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Pemetrexed/Carboplatin<br>Pemetrexed disodium 500 mg/m2 IV over 10 minutes and carboplatin to area under the curve (AUC) 5 IV over 30 minutes on day 1 of a 21-day cycle. | Drug: pemetrexed disodium<br>* 500 mg/m2 IV over 10 minutes on day 1 of a 21-day cycle<br>* Other names: LY231514;Drug: carboplatin<br>* Given by IV over 30 minutes at an area under the curve (AUC) of 5 on day 1 of a 21-day cycle<br>* Other names: NSC-241240;|
| Experimental: Pemetrexed/Gemcitabine<br>Pemetrexed disodium 500 mg/m2 IV over 10 minutes on day 1 and gemcitabine 1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21-day cycle. | Drug: pemetrexed disodium<br>* 500 mg/m2 IV over 10 minutes on day 1 of a 21-day cycle<br>* Other names: LY231514;Drug: gemcitabine hydrochloride<br>* 1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21-day cycle<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response by RECIST Criteria (Version 1.0) | Number of eligible, treated participants in each response category by RECIST criteria. Response categories represent best response for each patient prior to progression. | Assessed every 2 cycles (6 weeks) while on treatment, then every 3 months for 2 years, then every 6 months for 1 year until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death. Patients alive at last follow-up were censored. | Assessed every 3 months for 2 years, then every 6 months for 1 year | 
| Progression-Free Survival | Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored. | Assessed every 3 months for 2 years, then every 6 months for 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced malignant mesothelioma, recurrent malignant mesothelioma