Sorafenib and High-Dose Carboplatin, Paclitaxel, and External-Beam Radiation Therapy in Treating Patients With Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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. Giving sorafenib together with high-dose chemotherapy and external-beam radiation therapy may kill more tumor cells. PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of sorafenib when given together with high-dose carboplatin, paclitaxel, and external-beam radiation therapy in treating patients with stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary To determine the median survival from randomization for patients receiving carboplatin and paclitaxel with high-dose radiation therapy (HDRT) or same regimen with sorafenib tosylate. Secondary To determine the overall response rate, failure-free survival, and survival for patients receiving carboplatin/paclitaxel with 74 Gy HDRT or same regimen with sorafenib tosylate. To determine the feasibility of concurrent sorafenib tosylate and chemoradiation as measured by safety (the rate of grade 3 or higher radiation related esophagitis or pulmonary toxicity or chemotherapy related grade 4 hematological or other non-hematological toxicities occurring within 60 days of the start of treatment) and compliance (the completion of the treatment regimen with no more than minor variations). To correlate outcomes (survival, toxicity, quality of life) with biological parameters. OUTLINE: This is a multicenter study. Phase I: Chemoradiotherapy: Patients receive paclitaxel IV over 60 minutes and carboplatin IV over 30 minutes on day 1. Treatment repeats weekly for 7 weeks. Patients undergo concurrent high-dose external beam radiotherapy (HDRT) 5 days a week for 7.5 weeks. Cohorts of patients also receive escalating doses of oral sorafenib tosylate twice daily for 7 weeks. Consolidation therapy: Beginning at week 11, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 weeks. Patients also receive oral sorafenib tosylate at the maximum tolerated dose (MTD) twice daily. Maintenance: Patients receive oral sorafenib tosylate twice daily at the MTD. Phase II: Patients are randomized to 1 of 2 treatment arms. Arm I: Chemoradiotherapy: Patients receive paclitaxel, carboplatin, and HDRT as in phase I. Consolidation therapy: Patients receive paclitaxel and carboplatin as in phase I. Arm II: Chemoradiotherapy: Patients receive paclitaxel, carboplatin, and HDRT as in phase I. Patients also receive oral sorafenib tosylate as in phase I at the MTD. Consolidation therapy: Patients receive paclitaxel, carboplatin, and sorafenib tosylate at the MTD as in phase I. Maintenance: Patients receive sorafenib tosylate at the MTD as in phase I. After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for 2 years.

Official Title
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A Randomized Phase I/II Study Of Sorafenib In Combination With High Does Chemoradiation In Patients With Stage IIIA/B Non-small Cell Lung Cancer (NSCLC)

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel
* Drug: sorafenib tosylate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Inclusion criteria: Histologically or cytologically documented non-small cell lung cancer (NSCLC) Any of the following subtypes allowed: Adenocarcinoma (including bronchoalveolar cell) Squamous cell carcinoma Large cell anaplastic carcinoma (including giant and clear cell carcinomas) Poorly differentiated (not otherwise specified) NSCLC No metastasis (patients must be M0) Stage IIIA (T1 or T2 with N2 or T3N1-2) or stage IIIB (T4 with any N or any T with N2 or N3) disease Measurable disease Tumors adjacent to a vertebral body are allowed 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 Pleural effusion that is a transudate, cytologically negative, and nonbloody allowed if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy Pleural effusions seen on the chest CT but too small to tap allowed Exclusion criteria: Totally resected tumors Exudative, bloody, or cytologically malignant effusions Known brain metastasis Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis PATIENT CHARACTERISTICS: Inclusion criteria: Zubrod performance status 0-1 ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL (prior to transfusions) Total bilirubin ≤ 1.5 mg/dL AST or ALT ≤ 3 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Glucose ≤ 2 times ULN Creatinine ≤ 2.0 mg/dL FEV_1 ≥ 1,200 mL Weight loss ≤ 10% over the past 3 months Not pregnant or nursing Negative pregnancy test Women of childbearing potential and male participants who are unwilling or unable to use an acceptable method of contraception throughout the study and for 4 weeks after completion of treatment or those who are using a prohibited contraceptive method INR < 1.5 or a PT/PTT within normal limits Exclusion criteria: Known allergy to murine proteins or Cremophor EL Active pulmonary infection not responsive to conventional antibiotics History of severe chronic obstructive pulmonary disease requiring ≥ 3 hospitalizations over the past year Cardiac disease including any of the following: Congestive heart failure > class II NYHA Unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) Myocardial infarction within the past 6 months Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Patients with neuropathy > grade 1 Evidence of malignancy in the past 2 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other in situ cancer Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management Known HIV infection or chronic hepatitis B Active clinically serious infection > CTCAE grade 2 Thrombolic or embolic events, such as a cerebrovascular accident including transient ischemic attacks, within the past 6 months Pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks Any other hemorrhage or bleeding event ≥ CTCAE Grade 3 within the past 4 weeks Serious nonhealing wound, ulcer, or bone fracture Evidence or history of bleeding diathesis or coagulopathy Known or suspected allergy to sorafenib tosylate or any agent given in the course of this trial Any condition that impairs patient's ability to swallow whole pills Any malabsorption problem Significant traumatic injury within the past 4 weeks PRIOR CONCURRENT THERAPY: Inclusion criteria: Recovered from exploratory thoracotomy Concurrent anti-coagulation treatment with an agent such as warfarin or heparin allowed provided INR or PT/PTT requirements are met Exclusion criteria: Prior systemic chemotherapy for lung cancer and/or thoracic/neck radiotherapy for any reason Prior surgical resection of present cancer Prior therapy with any molecular-targeted drugs (for lung cancer) Currently participating in other phase III therapeutic clinical trials and/or who have participated in other phase III therapeutic clinical trials in the previous 30 days Major surgery or open biopsy within the past 4 weeks Concurrent Hypericum perforatum (St. John's wort) or rifampin (rifampicin) Other concurrent anticancer drugs, including hormonal, immunotherapeutic, or chemotherapeutic agents Steroids for acute symptom management, adrenal failure, septic shock, or as antiemetics allowed Hormones administered for nondisease-related conditions (e.g., insulin for diabetes) allowed Amifostine concurrently with radiotherapy or within 3 months of completion of radiotherapy Concurrent colony-stimulating factors (i.e., filgrastim [G-CSF] or sargramostim [GM-CSF])

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and high-dose external beam radiotherapy (HDRT) as in phase I. Patients also receive consolidation therapy comprising paclitaxel and carboplatin as in phase I. | Drug: carboplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Radiation: radiation therapy<br>* Given 5 days a week for 7.5 weeks<br>|
| Experimental: Arm II<br>Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and HDRT as in phase I. Patients also receive consolidation therapy comprising paclitaxel, carboplatin, and sorafenib tosylate at the MTD as in phase I, as well as maintenance therapy comprising sorafenib tosylate at the MTD as in phase I. | Drug: carboplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Drug: sorafenib tosylate<br>* Given orally<br>Radiation: radiation therapy<br>* Given 5 days a week for 7.5 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median survival | To determine the median survival from randomization for patients receiving carboplatin / paclitaxel with high dose radiation therapy or same regimen with Sorafenib. | Mean 24-Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | To determine the overall response rate, failure-free survival and survival for patients receiving carboplatin / paclitaxel with high dose radiation therapy or same regimen with Sorafenib. | Mean 24-Months | 

 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, recurrent non-small cell lung cancer, adenocarcinoma of the lung, squamous cell lung cancer, large cell lung cancer, bronchoalveolar cell lung cancer, adenosquamous cell lung cancer