TARCEVA (Erlotinib) in Combination With Chemoradiation in Patients With Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The goal of this clinical research study is to find out if erlotinib given with chemotherapy and radiation therapy can help to control NSCLC. The safety of this combination treatment will also be studied. Researchers will also test the tissue from your earlier biopsy to measure the levels of epidermal growth factor receptor (EGFR). The purpose of EGFR testing is to learn about any link between various forms of EGFR and your response to treatment with erlotinib.

Detailed Description
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Erlotinib is designed to block the activity of a protein called epidermal growth factor (EGFR). EGFR is found on the surface of many tumor cells that may control tumor growth and survival. This may stop tumors from growing. Before you can start treatment on this study, you will have screening tests. These tests will help the doctor decide if you are eligible to take part in the study. You will have a FEV1 (breathing test). You will have a complete physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). Blood (about 2 tablespoons) will be drawn for routine tests. You will have a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to check the status of the disease. You will be required to have a positron emission tomography (PET) scan to locate the area of cancer outside the chest and lymph glands. You will have either a CT scan or an MRI to measure the size of the tumor(s). If there is positive finding of CT or MRI you will be taken off study. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). If you have a significant history of cardiovascular disease, you will have a MUGA scan and echocardiogram to test your heart function. Women who are able to have children must have a negative urine or blood (about 2 teaspoons) pregnancy test before starting treatment. You will have PET scan 1 month after completion of consolidation chemotherapy. If you are found to be eligible to take part in this study, you will take erlotinib every day for 7 weeks (except on the days you receive chemotherapy). The erlotinib tablets should be taken at the same time each day, at least 1 hour before or 2 hours after a meal, with a small glass (about 7 ounces) of water. If you are unable to swallow tablets, you may dissolve the tablets in distilled water to drink. You will receive radiation every day (Monday through Friday) for 7 weeks. You will also receive chemotherapy through a needle in a vein once a week for 7 weeks. The chemotherapy will include carboplatin and paclitaxel. Receiving chemotherapy will take about 6 hours total. You will receive consolidation therapy on weeks 11-17. Treatment on this study will last 17 weeks. Once a week during that time, you will have blood (about 2 tablespoons) drawn for routine tests. You will also have a CT scan of the chest within about 4 weeks from beginning the study, 2 months after finishing therapy, and then every 6 months after that for 2 years. The CT scans are used to check the status of the disease. You will be taken off study if the disease gets worse or intolerable side effects occur. In this case, you would not receive erlotinib anymore but would continue standard chemotherapy and radiation therapy. You will be asked to come in to the clinic for follow-up visits to check on your recovery from treatment. The follow-up visits will be at the end of all treatment, 1 month after treatment, and then once a month for as long as your doctor feels it is necessary. Once your side effects have become less severe, you will be asked to come in to the clinic for follow-up visits every 3 months for 2 years, and then every 4 months for the following 2 years after that. You will have a physical exam, and your medical history will be recorded. You will be asked about any side effects you may have. Blood (about 2 tablespoons) will be drawn for routine tests. You will have a PET scan. You have the right to leave the study at any time. If you choose to stop participating in this study, you should contact the study chair and/or research nurse. Your doctor may decide to take you off this study if your medical condition gets worse and/or you are unable to comply with study requirements. At the end of the study you will not be automatically notified of the research findings. If you wish to learn about the results, however, you may request them from the study chair. This is an investigational study. All three study drugs are commercially available. Carboplatin, and paclitaxel are FDA approved for the treatment of NSCLC, but their use in combination with erlotinib is not. Erlotinib is FDA approved for some uses, but it has not been approved by the FDA to treat lung cancer patients like yourself who have not yet undergone chemotherapy; however, the FDA has permitted its use in this research study. Carboplatin and paclitaxel are considered standard of care treatment and you would probably be treated with these drugs or similar drugs even if you decided not to be in the study. Up to 48 patients will take part in this study. All will be enrolled at M. D. Anderson.

Official Title
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A Phase II Study of TARCEVA (Erlotinib) in Combination With Chemoradiation in Patients With Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer, Lung Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented NSCLC, including squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell), and large cell anaplastic carcinoma (including giant and clear cell carcinomas) and poorly differentiated (not otherwise specified, NOS) non-small cell lung cancer; totally resected tumors are excluded. · Patients must be M0; Patients with Tl or T2 disease with N2 or T3N1-2 disease (Stage IIIA) are eligible if they are deemed inoperable. Patients with T4 with any N or any T with N2 or N3 disease are eligible if unresectable. Radiographic evidence of mediastinal lymph nodes > 2.0 cm in the largest diameter is sufficient to stage N2 or N3 disease. If the largest mediastinal node is < 2.0 cm in diameter and this is the basis for stage III disease, then at least one of the nodes must be proven positive cytologically or histologically; Measurable disease is required Patients with tumors adjacent to a vertebral body are eligible as long as all gross disease can be encompassed in the radiation boost field. The boost volume must be limited to < 50% of the ipsilateral lung volume. Patients must be greater than or equal to 18 years of age; Patients with Zubrod performance status 0-1 Adequate hematologic function defined as: ANC greater than or equal 1,500/mm^3, platelets greater than or equal 100,000/mm^3, and hemoglobin greater than or equal 9 g/dL (prior to transfusions); adequate hepatic function defined as: total bilirubin less than or equal to 1.5 mg/dl, SGOT or SGPT less than or equal to 3 x ULN, adequate renal function defined as a serum creatinine level less than or equal to 2.0 mg/dl, alkaline phosphatase less than or equal to 2.5 x ULN, glucose less than or equal to 2 x ULN; FEV1 with greater than or equal to 1000 cc; Patients with weight loss less than or equal to than </= 10% over the past 3 months; Patients with a pleural effusion that is a transudate, cytologically negative and nonbloody are eligible if the radiation oncologists feel the tumor can still 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 is eligible. If patients had exploratory thoracotomy, they must have recovered from the procedure. Exploratory Thoracotomy and beginning of treatment should be within one month. Women of childbearing potential (A woman of child-bearing potential is a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months [i.e., who has had menses at any time in the preceding 24 consecutive months]) and male participants must practice effective contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for four weeks after completion of treatment. For women of childbearing potential, a urine or blood pregnancy test must be performed within 48 hours prior to the start of protocol treatment; Medical Oncology and Radiation Oncology consults and approval. Patients must sign a study-specific consent form prior to study entry. Exclusion Criteria: Prior systemic chemotherapy and/or thoracic radiotherapy for any reason and/or surgical resection of present cancer; Exudative, bloody, or cytologically malignant effusion or effusion that are exudative and/or bloody and are suggestive or malignant involvement. Prior therapy with any other drug that targets the EGFR pathway, Active pulmonary infection not responsive to conventional antibiotics; History of interstitial lung disease; History of severe COPD requiring greater than or equal to 3 hospitalizations over the past year; Significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, uncompensated congestive heart failure, myocardial infarction within the past year, or cardiac ventricular arrhythmias requiring medication; patients with left ventricular ejection fraction (LVEF) below the institutional range of normal (50-70%) on a baseline multiple gated acquisition (MUGA) scan or echocardiogram. Patients with > grade 1 neuropathy; Evidence of malignancy in the past 3 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other in situ cancers; Women who are pregnant or breast feeding, as treatment involves unforeseeable risks to the participant, embryo, fetus, or nursing infant; women with a positive pregnancy test on enrollment or prior to study drug administration; Women of childbearing potential and male participants who are unwilling or unable to use an acceptable method of contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for four weeks after completion of treatment or those who are using a prohibited contraceptive method (methods with unknown efficacy). Patients who currently are participating in other clinical trials and/or who have participated in other clinical trials in the previous 30 days. Clinical trials involving administration of investigational agents or interfering with the safe conduct of this trial. All clinical trials would exclude observational trials which would not interfere with the endpoints of our study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib + Paclitaxel + Carboplatin<br>Oral Erlotinib 150 mg daily + Paclitaxel 45 mg/m^2 by vein weekly + Carboplatin 2 AUC by vein weekly and Radiation Therapy 63 GY/35 fractions for 7 weeks cycles | Drug: Erlotinib<br>* 150 mg by mouth daily for 7 Weeks<br>* Other names: Erlotinib Hydrochloride;Drug: Carboplatin<br>* 2 AUC by vein weekly for 7 Weeks<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* 45 mg/m^2 by vein weekly for 7 Weeks<br>* Other names: Taxol;Radiation: Radiation Therapy<br>* 63 GY/35 fractions for 7 weeks (+/- 5 days)<br>* Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To First Disease Progression | Primary Endpoints is efficacy of concurrent erlotinib and chemoradiation as measured by time to progression. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions. All patients will be evaluated by followed up one month after treatment, once a month until recovery from treatment related toxicities, then every 3 months for 2 years, then every 4 months for 2 years (total of 4 years), then annually up to 5 years. | From date of registration until the date of first documented progression or death from any cause, or lost to follow up, whichever came first, assessed up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival and Disease Local Control Rate | The Secondary Endpoints is Overall Survival (OS)and Disease Local Control (DLC)Rate. All patients will be followed up to evaluate Overall Survival and Disease Local Control by one month after treatment, once a month until recovery from treatment related toxicities, then every 3 months for 2 years, then every 4 months for 2 years (total of 4 years), then annually up to 5 years. CT scan of the chest/upper abdomen, MRI of brain or CT, and/or PET scan images are recommended to confirm the recurrence. Survival endpoints were estimated using the Kaplan-Meier method. | OS: From date of registration until the date of first documented death or lost to follow up, whichever came first, accessed up to 5 years. DLC: From date of registration until the date of first documented local disease recurrence, accessed up to 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer, Lung Cancer, Squamous Cell Carcinoma, Adenocarcinoma, Bronchoalveolar Cell Carcinoma, Large Cell Anaplastic Carcinoma, Giant Cell Carcinoma, Clear Cell Carcinoma, Erlotinib, Erlotinib Hydrocholoride, OSI-774, Tarceva, Carboplatin, Paraplatin, Paclitaxel, Taxol, NSCLC