Mesothelioma
Conditions
Keywords
advanced malignant mesothelioma, recurrent malignant mesothelioma
Brief summary
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
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.
Interventions
DRUGpemetrexed disodium
500 mg/m2 IV over 10 minutes on day 1 of a 21-day cycle
DRUGgemcitabine hydrochloride
1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21-day cycle
DRUGcarboplatin
Given by IV over 30 minutes at an area under the curve (AUC) of 5 on day 1 of a 21-day cycle
Sponsors
National Cancer Institute (NCI)
North Central Cancer Treatment Group
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response by RECIST Criteria (Version 1.0) | 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 | Number of eligible, treated participants in each response category by RECIST criteria. Response categories represent best response for each patient prior to progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Assessed every 3 months for 2 years, then every 6 months for 1 year | Time from randomization to death. Patients alive at last follow-up were censored. |
| Progression-Free Survival | Assessed every 3 months for 2 years, then every 6 months for 1 year | Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored. |
Countries
United States
Participant flow
Recruitment details
The study was activated on November 1, 2005, accrued its first patient on February 23, 2006, suspended to accrual on July 12, 2007 for response evaluation, and closed to accrual on April 1, 2008.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed/Carboplatin Pemetrexed disodium 500 mg/m2 IV over 10 minutes and carboplatin to AUC 5 IV over 30 minutes on day 1 of a 21-day cycle. | 16 |
| Pemetrexed/Gemcitabine 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. | 13 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Insurance Refusal | 0 | 1 |
| Overall Study | Prostate Cancer Recurrence | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Pemetrexed/Carboplatin | Pemetrexed/Gemcitabine | Total |
|---|---|---|---|
| Age, Continuous | 72 years | 68 years | 71 years |
| Sex: Female, Male Female | 2 Participants | 12 Participants | 14 Participants |
| Sex: Female, Male Male | 14 Participants | 1 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 13 / 13 |
| serious Total, serious adverse events | 10 / 16 | 13 / 13 |
Outcome results
Primary
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.
Time frame: 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
Population: The population consisted of all eligible, treated patients. 3 patients randomized to pemetrexed/gemcitabine who withdrew prior to treatment are excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin | Best Overall Response by RECIST Criteria (Version 1.0) | Partial Response | 3 eligible, treated participants |
| Pemetrexed/Carboplatin | Best Overall Response by RECIST Criteria (Version 1.0) | Stable Disease | 7 eligible, treated participants |
| Pemetrexed/Carboplatin | Best Overall Response by RECIST Criteria (Version 1.0) | Progression | 5 eligible, treated participants |
| Pemetrexed/Carboplatin | Best Overall Response by RECIST Criteria (Version 1.0) | Unevaluable | 1 eligible, treated participants |
| Pemetrexed/Gemcitabine | Best Overall Response by RECIST Criteria (Version 1.0) | Unevaluable | 2 eligible, treated participants |
| Pemetrexed/Gemcitabine | Best Overall Response by RECIST Criteria (Version 1.0) | Partial Response | 0 eligible, treated participants |
| Pemetrexed/Gemcitabine | Best Overall Response by RECIST Criteria (Version 1.0) | Progression | 5 eligible, treated participants |
| Pemetrexed/Gemcitabine | Best Overall Response by RECIST Criteria (Version 1.0) | Stable Disease | 6 eligible, treated participants |
Comparison: The treatment was to be considered promising if a true response rate of 40% or higher was observed, whereas a rate of 15% or less would not be of interest. 3 or more responses were required to expand accrual to a second stage. This expansion did not occur.90% CI: [5.4, 41.7]
Comparison: The treatment was to be considered promising if a true response rate of 40% or higher was observed, whereas a rate of 15% or less would not be of interest. 3 or more responses were required to expand accrual to a second stage. This expansion did not occur.90% CI: [0, 20.6]
Secondary
Overall Survival
Time from randomization to death. Patients alive at last follow-up were censored.
Time frame: Assessed every 3 months for 2 years, then every 6 months for 1 year
Population: The population consisted of all eligible, treated patients. 3 patients randomized to pemetrexed/gemcitabine who withdrew prior to treatment are excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Overall Survival | 13.0 Months |
| Pemetrexed/Gemcitabine | Overall Survival | 6.0 Months |
Secondary
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.
Time frame: Assessed every 3 months for 2 years, then every 6 months for 1 year
Population: The population consisted of all eligible, treated patients. 3 patients randomized to pemetrexed/gemcitabine who withdrew prior to treatment are excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Progression-Free Survival | 4.1 Months |
| Pemetrexed/Gemcitabine | Progression-Free Survival | 3.3 Months |