Pemetrexed Disodium, Carboplatin, and Radiation Therapy With or Without Cetuximab in Treating Patients With Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase II Study of Radiation Therapy, Pemetrexed and Carboplatin With or Without Cetuximab in Stage III Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: carboplatin
* Drug: pemetrexed disodium
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Histologically or cytologically documented NSCLC, including squamous cell carcinoma, adenocarcinoma including bronchoalveolar cell, and large cell anaplastic carcinoma (including giant and clear cell carcinomas) 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. 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. 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 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. 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 ECOG performance status 0-1 Positron Emission Tomography (PET) using 18 fluorodeoxyglucose (FDG) must be negative for distant metastasis. PET imaging is mandatory. Weight loss of ≤ 10% in the past 3 months 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. Non-pregnant and non-nursing because of significant risk to the fetus/infant Age ≥ 18 years 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. 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 No known history of hypersensitivity to carboplatin, pemetrexed or a monoclonal antibody Required Initial Laboratory Values: Granulocytes ≥ 1,500/mcl Platelets ≥ 100,000/mcl Calculated Creatinine Clearance ≥ 45 ml/min Bilirubin < 1.5 x ULN AST/ALT < 3 x ULN Alkaline Phosphatase < 3 x ULN

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: Std Tx + Pemetrexed<br>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. | Drug: carboplatin<br>* AUC = 5 q 21 days for 4 cycles<br>Drug: pemetrexed disodium<br>* 500 mg/sq m IV q 21 days during chemoradiation and consolidation chemotherapy phases<br>Radiation: radiation therapy<br>* Thoracic radiotherapy: 70 Gy for 7 weeks beginning on Day 1.<br>|
| Experimental: Std Tx + Pemetrexed and Cetuximab<br>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. | Biological: cetuximab<br>* 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.<br>Drug: carboplatin<br>* AUC = 5 q 21 days for 4 cycles<br>Drug: pemetrexed disodium<br>* 500 mg/sq m IV q 21 days during chemoradiation and consolidation chemotherapy phases<br>Radiation: radiation therapy<br>* Thoracic radiotherapy: 70 Gy for 7 weeks beginning on Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 18 months (from randomization) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 from randomization to failure (up to 4 years) | 
| 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. | Duration of study until progression (up to 4 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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