Lung Cancer
Conditions
Keywords
stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, squamous cell lung cancer, large cell lung cancer, adenocarcinoma of the lung, bronchoalveolar cell lung cancer
Brief summary
RATIONALE: Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also make tumor cells more sensitive to radiation therapy. Giving pemetrexed disodium, carboplatin, and radiation therapy together with cetuximab may kill more tumor cells. PURPOSE: This randomized phase II trial is studying how well giving pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery.
Detailed description
OBJECTIVES: Primary * Determine the overall survival of patients with unresectable stage III non-small cell lung cancer treated with pemetrexed disodium, carboplatin, and thoracic radiotherapy with or without cetuximab. Secondary * Determine the failure-free survival and response rates in patients treated with these regimens. * Correlate epidermal growth factor receptor, erbB2, and K-ras mutations with survival and tumor response in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. * Chemoradiotherapy (courses 1-4): Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive pemetrexed disodium IV over 10 minutes followed by carboplatin IV over 30 minutes on days 1, 22, 43, and 64. Patients also undergo thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. * Arm II: Patients receive pemetrexed disodium, carboplatin, and thoracic radiotherapy as in arm I. Patients also receive cetuximab IV over 2 hours on day 1 and then IV over 1 hour on days 8, 15, 22, 29, 36, and 43. * Consolidation chemotherapy (courses 5-8): Beginning 3-5 weeks after completion of chemoradiotherapy, all patients receive consolidation chemotherapy comprising pemetrexed disodium alone IV over 10 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this study within 10-13 months.
Interventions
BIOLOGICALcetuximab
400 mg/sq m IV over 120 min: Day 1; Week 1 250 mg/sq m IV over 60 min weekly for 6 more weeks.
DRUGcarboplatin
AUC = 5 q 21 days for 4 cycles
DRUGpemetrexed disodium
500 mg/sq m IV q 21 days during chemoradiation and consolidation chemotherapy phases
RADIATIONradiation therapy
Thoracic radiotherapy: 70 Gy for 7 weeks beginning on Day 1.
Sponsors
National Cancer Institute (NCI)
Eli Lilly and Company
Bristol-Myers Squibb
Alliance for Clinical Trials in Oncology
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
1. Histologically or cytologically documented NSCLC, including squamous cell carcinoma, adenocarcinoma including bronchoalveolar cell, and large cell anaplastic carcinoma (including giant and clear cell carcinomas) 2. Eligible Disease Stages: Inoperable IIIA and Selected IIIB - Patients entered must be considered unresectable or inoperable. Patients do not need to have a mediastinoscopy. A size of 2 cm or greater by CT is a sufficient criterion for the diagnosis of mediastinal lymph node (N2 or N3) involvement by malignancy. If the largest mediastinal lymph node is less than 2 cm in diameter, a biopsy confirmation of mediastinal nodal involvement is required. 1. The following patients are eligible: * Patients must be M0 * Patients with any T with N2 or N3 are eligible * Patients with T3, N1-N3 disease are eligible if deemed unresectable * Patients with T4, any N are eligible provided the T4 status is not determined because of malignant effusion * Patients with contralateral mediastinal disease (N3) are eligible if all gross disease can be encompassed in the radiation field in accordance with the homogeneity criteria * Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy * If a pleural effusion can be seen on the chest CT but not on CXR and is too small to tap, the patient will be eligible. Patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible. 2. The following patients are NOT eligible: * Patients with T3, N0 disease * Patients with M1 disease * Patients with atelectasis of the entire lung * Patients with direct invasion of vertebral body * Patients with scalene, supraclavicular, or contralateral hilar node involvement * Patients with exudative, bloody, or cytologically malignant effusions 3. Patients must have Measurable Disease: Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan. Lesions that are not considered measurable include bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions and tumor lesions situated in a previously irradiated area. 4. Prior Therapy: ≥ 2 weeks since formal exploratory thoracotomy. No prior chemotherapy for NSCLC, chest radiation therapy or therapy that specifically and directly targets the EGFR pathway 5. ECOG performance status 0-1 6. Positron Emission Tomography (PET) using 18 fluorodeoxyglucose (FDG) must be negative for distant metastasis. PET imaging is mandatory. 7. Weight loss of ≤ 10% in the past 3 months 8. No currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse. 9. Non-pregnant and non-nursing because of significant risk to the fetus/infant 10. Age ≥ 18 years 11. No patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness. 12. No HIV-positive patients receiving combination anti-retroviral therapy because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy 13. No known history of hypersensitivity to carboplatin, pemetrexed or a monoclonal antibody 14. Required Initial Laboratory Values: 1. Granulocytes ≥ 1,500/mcl 2. Platelets ≥ 100,000/mcl 3. Calculated Creatinine Clearance ≥ 45 ml/min 4. Bilirubin \< 1.5 x ULN 5. AST/ALT \< 3 x ULN 6. Alkaline Phosphatase \< 3 x ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 18 Month Survival | 18 months (from randomization) | Percentage of participants who were alive at 18 months. The 18 month survival, with 95% CI, was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Failure-free Survival | Time from randomization to failure (up to 4 years) | Failure-free survival (FFS) is the time from randomization to a failure event, defined as disease progression or death from any cause (which ever occurred first). The median FFS with 95% CI was estimated using the Kaplan-Meier method, |
| Number of Participants With Overall Tumor Response | Duration of study until progression (up to 4 years) | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Complete Response (CR): disappearance of all target lesions; * Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; * Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; * Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Time from randomization to death (up to 4 years) | Overall survival (OS) is defined as the time from patient randomization (arm assignment) to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method. |
Countries
United States
Participant flow
Recruitment details
Between September 2005 and January 2008, 109 participants were recruited.
Pre-assignment details
Six (6) participants cancelled before receiving any protocol related therapy and 2 participants were deemed ineligible; therefore, 101 participants were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Std Tx + Pemetrexed Patients receive pemetrexed disodium IV over 10 minutes followed by carboplatin IV over 30 minutes on days 1, 22, 43, and 64. Patients also undergo thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. | 48 |
| Std Tx + Pemetrexed and Cetuximab Patients receive pemetrexed disodium, carboplatin, and thoracic radiotherapy as in arm I. Patients also receive cetuximab IV over 2 hours on day 1 and then IV over 1 hour on days 8, 15, 22, 29, 36, and 43. | 53 |
| Total | 101 |
Baseline characteristics
| Characteristic | Std Tx + Pemetrexed and Cetuximab | Total | Std Tx + Pemetrexed |
|---|---|---|---|
| Age, Continuous | 66 years | 66 years | 65 years |
| ECOG Performance Status 0 - Fully Active | 18 participants | 46 participants | 28 participants |
| ECOG Performance Status 1 - Ambulatory, restricted strenuous activity | 35 participants | 55 participants | 20 participants |
| Histology Adenocarcinoma | 22 participants | 44 participants | 22 participants |
| Histology Large cell | 2 participants | 2 participants | 0 participants |
| Histology Not reported | 1 participants | 2 participants | 1 participants |
| Histology NSCLC, undifferentiated | 10 participants | 18 participants | 8 participants |
| Histology Squamous | 18 participants | 35 participants | 17 participants |
| Region of Enrollment United States | 53 participants | 101 participants | 48 participants |
| Sex: Female, Male Female | 19 Participants | 40 Participants | 21 Participants |
| Sex: Female, Male Male | 34 Participants | 61 Participants | 27 Participants |
| TNM Stage IIIA | 27 participants | 56 participants | 29 participants |
| TNM Stage IIIB | 24 participants | 42 participants | 18 participants |
| TNM Stage Not reported | 2 participants | 3 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 48 / 50 | 50 / 53 |
| serious Total, serious adverse events | 21 / 50 | 25 / 53 |
Outcome results
Primary
18 Month Survival
Percentage of participants who were alive at 18 months. The 18 month survival, with 95% CI, was estimated using the Kaplan-Meier method.
Time frame: 18 months (from randomization)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Std Tx + Pemetrexed | 18 Month Survival | 58 percentage of participants |
| Std Tx + Pemetrexed and Cetuximab | 18 Month Survival | 54 percentage of participants |
Secondary
Failure-free Survival
Failure-free survival (FFS) is the time from randomization to a failure event, defined as disease progression or death from any cause (which ever occurred first). The median FFS with 95% CI was estimated using the Kaplan-Meier method,
Time frame: Time from randomization to failure (up to 4 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Std Tx + Pemetrexed | Failure-free Survival | 12.6 months |
| Std Tx + Pemetrexed and Cetuximab | Failure-free Survival | 12.3 months |
Secondary
Number of Participants With Overall Tumor Response
Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Complete Response (CR): disappearance of all target lesions; * Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; * Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; * Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs.
Time frame: Duration of study until progression (up to 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Std Tx + Pemetrexed | Number of Participants With Overall Tumor Response | 37 participants |
| Std Tx + Pemetrexed and Cetuximab | Number of Participants With Overall Tumor Response | 38 participants |
Other Pre-specified
Overall Survival
Overall survival (OS) is defined as the time from patient randomization (arm assignment) to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Time frame: Time from randomization to death (up to 4 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Std Tx + Pemetrexed | Overall Survival | 21.2 months |
| Std Tx + Pemetrexed and Cetuximab | Overall Survival | 25.2 months |