Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This clinical trial studies combination chemotherapy, radiation therapy, and bevacizumab in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as cisplatin, etoposide, and docetaxel, work in different ways to stop the growth of [cancer/tumor] cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with radiation therapy and bevacizumab may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the frequency and severity of toxic effects of induction therapy comprising cisplatin, etoposide, and radiotherapy with or without bevacizumab followed by consolidation therapy comprising docetaxel and bevacizumab, in terms of grade 4 or 5 hemorrhage, in patients with newly diagnosed, unresectable, stage III non-small cell lung cancer. SECONDARY OBJECTIVES: I. Determine progression-free and overall survival of patients treated with these regimens. II. Determine response (confirmed, unconfirmed, partial, and complete) in patients with measurable disease treated with these regimens. OUTLINE: This is a pilot, multicenter study. Patients are stratified according to risk (high* vs low). NOTE: *High-risk stratum closed to accrual as of 2/20/09. INDUCTION THERAPY: Patients in each stratum are assigned to 1 of 3 sequential treatment groups. GROUP 1: Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 29, and 36 and etoposide IV over 1 hour on days 1-5 and 29-33. Patients undergo concurrent thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. GROUP 2: Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 15, 36, and 57. GROUP 3: Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 1, 22, and 43. CONSOLIDATION CHEMOTHERAPY: Beginning 3-6 weeks after completion of induction therapy, all patients receive consolidation chemotherapy comprising docetaxel IV over 1 hour and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 2 and continuing until blood counts recover OR pegfilgrastim SC once on day 2. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 4 years.

Official Title
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A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Addition of Bevacizumab (NSC-704865) in Three Cohorts of Patients With Inoperable Locally Advanced Stage III Non-small Cell Lung Cancer

Conditions
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Lung Adenocarcinoma, Lung Adenosquamous Carcinoma, Lung Large Cell Carcinoma, Lung Squamous Cell Carcinoma, Minimally Invasive Lung Adenocarcinoma, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Cisplatin
* Drug: Docetaxel
* Drug: Etoposide
* Biological: Filgrastim
* Biological: Pegfilgrastim
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed single, primary, bronchogenic, non-small cell lung cancer (NSCLC) Newly diagnosed disease Unresectable disease No more than 1 parenchymal lesions on same or opposite sides of the lungs Meets 1 of the following stage criteria: Stage IIIA (N2) disease meeting the following criteria: N2 mediastinal lymph nodes must be multiple and/or bulky on CT scan or x-ray so that the patient is not a candidate for induction chemotherapy or chemoradiotherapy followed by surgical resection N2 status must be documented by ≥ 1 of the following methods: Histologically or cytologically confirmed N2 disease by exploratory thoracotomy, thoracoscopy, mediastinoscopy, mediastinotomy, Chamberlain procedure, Wang needle biopsy (WNB), fine needle aspiration (FNA) under bronchoscopic or CT guidance, or any other method Node positive by fludeoxyglucose-positron emission tomography (FDG-PET) scan Nodes > 3 cm on CT scan Paralyzed left true vocal cord with separate left lung primary distinct from anterior-posterior window nodes on CT scan Stage IIIB disease meeting ≥ 1 of the following criteria: Histologically or radiographically confirmed positive N3 nodes*, documented by ≥ 1 of the following methods: FNA, core needle biopsy (CNB), or excisional biopsy of supraclavicular N3 nodes Biopsy of contralateral mediastinal N3 nodes by mediastinoscopy, mediastinotomy, or thoracotomy FNA, CNB, or WNB under CT or bronchoscopic fluoroscopic guidance of enlarged contralateral N3 mediastinal nodes Contralateral mediastinal nodes > 3 cm on CT scan Node positivity by FDG-PET scan Right-sided primary with paralyzed left true vocal cord T4 lesions of any size that invade the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina, documented by ≥ 1 of the following methods: Written documentation of type of T4 extent if patient had a prior exploratory thoracotomy or thoracoscopy T4 involvement of the trachea or carina by direct bronchoscopic visualization T4 involvement of the heart, esophagus, aorta, or vertebral body by CT scan, MRI, or transesophageal ultrasound T4 involvement of the mediastinum by CT scan or MRI if, in the absence of the above organ involvement, there is soft tissue extension directly into the mediastinal space** Meets 1 of the following risk criteria: Low risk disease, meeting the following criteria: Non-squamous cell NSCLC, including adenocarcinoma, bronchoalveolar cell carcinoma, or large cell carcinoma If mixed histology, the squamous cell carcinoma component must be < 50% Histology or cytology from involved mediastinal or supraclavicular lymph nodes allowed if a separate distal primary lesion is clearly evident on radiographs (i.e., second biopsy not required) No primary tumor with cavitation and/or tumor within 1 cm of a major vessel No hemoptysis (i.e., bright red blood ≥ ½ teaspoon) in the past 28 days High-risk* disease, meeting ≥ 1 of the following criteria: Squamous cell NSCLC If mixed histology, the squamous cell component must be ≥ 50% Tumor with any histology that has cavitation or is located within 1 cm of a major vessel No aortic involvement Any histology and hemoptysis (i.e., bright red blood ≥ ½ teaspoon) within past 28 days Measurable or nonmeasurable disease by CT scan or MRI Pleural effusions, ascites, and laboratory parameters are not acceptable as the only evidence of disease No pleural effusion except for small pleural effusion visible on CT scan or MRI alone No pericardial effusions No metastatic disease involving the contralateral chest, liver, or adrenals confirmed by CT scan of the upper abdomen or by chest CT scan with complete liver and adrenals in the report Patients must be offered participation in SWOG-S9925 (Lung Cancer Specimen Repository Protocol) No brain metastases by CT scan or MRI No evidence of cavitation Creatinine normal Creatinine clearance ≥ 50 mL/min FEV_1 ≥ 2.0 liters OR predicted FEV_1 of the contralateral lung > 800 mL Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Urine protein: creatinine ratio ≤ 0.5 by urinalysis OR urine protein < 1,000 mg by 24-hour urine collection INR < 1.5 Zubrod performance status 0-1 No sensory neuropathy > grade 1 No cerebrovascular accident within the past 6 months No myocardial infarction or unstable angina within the past 6 months No uncontrolled hypertension No New York Heart Association class II-IV congestive heart failure No serious cardiac arrhythmia requiring medication No clinically significant peripheral vascular disease No evidence of bleeding diathesis or coagulopathy No pathologic condition other than lung cancer that carries a high risk of bleeding No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No serious, nonhealing wound, ulcer, or bone fracture No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer for which the patient is currently in complete remission, or other cancer for which the patient has been disease-free for 5 years Not pregnant or nursing No nursing during and for ≥ 6 months after the last dose of bevacizumab Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 6 months after the last dose of bevacizumab Must have pre-treatment simulation demonstrating a V20 ≤ 35% with planned radiation dose of 6,480 cGy No prior surgical resection Prior exploratory thoracotomy, mediastinoscopy, excisional biopsy, or similar surgery allowed for diagnosing, staging, or determining potential resectability of lung tumor No prior chemotherapy or radiotherapy for lung cancer No prior radiotherapy to the neck or thorax At least 4 weeks since prior thoracic or other major surgery (excluding mediastinoscopy) and recovered More than 7 days since prior FNA, CNB, or mediastinoscopy No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or biologic agents No other concurrent investigational drugs No concurrent major surgical procedures No concurrent full-dose anticoagulants (e.g., low-molecular weight and unfractionated heparin or warfarin) Low-dose warfarin (i.e., 1 mg) is allowed to prevent clotting of an infusaport or central line No concurrent brachytherapy, radiopharmaceuticals, high linear energy transfer radiation (i.e., fast neutrons), particle therapy (i.e., protons, carbon, or helium), and/or altered fractionation schemes No concurrent intensity-modulated radiotherapy No concurrent prophylactic contralateral hilar or supraclavicular lymph node radiotherapy

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (cisplatin, etoposide, radiotherapy)<br>Patients receive cisplatin IV over 1 hour on days 1, 8, 29, and 36 and etoposide IV over 1 hour on days 1-5 and 29-33. Patients undergo concurrent thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given SC<br>* Other names: Zarxio;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: Ziextenzo;Radiation: Radiation Therapy<br>* Undergo thoracic radiotherapy<br>* Other names: Therapy, Radiation;|
| Experimental: Group 2 (cisplatin, etoposide, radiotherapy, bevacizumab)<br>Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 15, 36, and 57. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given SC<br>* Other names: Zarxio;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: Ziextenzo;Radiation: Radiation Therapy<br>* Undergo thoracic radiotherapy<br>* Other names: Therapy, Radiation;|
| Experimental: Group 3 (cisplatin, etoposide, radiotherapy, bevacizumab)<br>Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 1, 22, and 43. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given SC<br>* Other names: Zarxio;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: Ziextenzo;Radiation: Radiation Therapy<br>* Undergo thoracic radiotherapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | From date of registration to time of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. | Disease assessments were performed every 10 weeks as long as the patient remained on protocol treatment, up to 4 years. | 
| Overall Survival | From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. | Every week, up to 4 years | 
| Response Rate (Confirmed or Unconfirmed Partial Response) | Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. | Response assessment occured at the end of CRT and docetaxel/bevacizumab and then every 2-3 months for 2 years and then every 6 months until 4 years after the initial registration |