Radiation Therapy, Bevacizumab, Paclitaxel, and Carboplatin in Treating Patients With Unresectable Stage IIIB or Stage IV Non-Small Cell Lung Cancer at High Risk for Hemoptysis Caused by Bevacizumab
Radiation Therapy, Bevacizumab, Paclitaxel, and Carboplatin in Treating Patients With Unresectable Stage IIIB or Stage IV Non-Small Cell Lung Cancer at High Risk for Hemoptysis Caused by Bevacizumab
This phase II trial is studying the side effects and how well giving radiation therapy
 together with bevacizumab, paclitaxel, and carboplatin works in treating patients with
 unresectable stage IIIB or stage IV non-small cell lung cancer at high risk for hemoptysis
 caused by bevacizumab. Radiation therapy uses high-energy x-rays to kill tumor cells. It may
 also prevent hemoptysis caused by bevacizumab. Monoclonal antibodies, such as bevacizumab,
 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.
 Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to
 the tumor. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different
 ways to stop the growth of tumor cells, either by killing the cells or by stopping them from
 dividing. Giving radiation therapy together with bevacizumab and chemotherapy may kill more
 tumor cells
PRIMARY OBJECTIVES:

 I. Evaluate the safety of prophylactic chest radiotherapy, bevacizumab, paclitaxel, and
 carboplatin in patients with unresectable stage IIIB or IV non-small cell lung cancer at high
 risk for bevacizumab-associated hemoptysis.

 SECONDARY OBJECTIVES:

 I. Assess progression-free survival of patients treated with this regimen. II. Assess the
 rate of objective response, overall survival, time to response, and response duration in
 irradiated lesions and non-irradiated lesions in these patients.

 OUTLINE: This is an open-label, pilot, multicenter study. Patients are assigned sequentially
 to 1 of 2 treatment strata.

 Stratum I: Patients undergo prophylactic radiotherapy on days 1-5 and 8-12. Patients receive
 paclitaxel IV over 3 hours and carboplatin IV over 30-60 minutes on day 15. Patients also
 receive paclitaxel IV over 3 hours or carboplatin IV over 30-60 minutes and bevacizumab IV
 over 30-90 minutes on day 36 (course 2).

 Stratum II: Patients undergo prophylactic radiotherapy and receive paclitaxel and carboplatin
 as in stratum I. Patients also receive bevacizumab IV over 30-90 minutes on day 15 (course
 1). In both strata, treatment with paclitaxel, carboplatin, and bevacizumab repeats every 21
 days for 5-6 courses in the absence of disease progression or unacceptable toxicity. Patients
 with complete or partial response or stable disease may continue to receive single-agent
 bevacizumab every 21 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed periodically for 12 months.

 PROJECTED ACCRUAL: A total of 72 patients will be accrued for this study.
Inclusion Criteria:

 -  Histologically or cytologically confirmed primary non-small cell lung cancer (NSCLC)*
 meeting the following criteria:

 -  Squamous cell or mixed squamous-nonsquamous histology with predominant squamous
 component (≥ 50% squamous) with a primary, unresected endobronchial lesion

 -  No small cell component

 -  Centrally located primary tumor, defined by the following:

 -  Primary tumor of any T stage within or touching the zone of the proximal
 bronchial tree

 -  Zone is defined as a 3-dimensional volume with a perimeter of 2 cm in
 each direction around the proximal bronchial tree (carina, right and
 left main bronchi, right and left upper lobe bronchi, intermedius
 bronchus, right middle lobe bronchus, lingular bronchus, right and left
 lower lobe bronchi)

 -  Any disease within this volume must not invade blood vessels determined
 by a contrast-enhanced CT scan evaluation of the entire thorax with
 thin slices (≤ 5 mm) through the area of central tumor bulk (i.e., no
 evidence of vessel invasion radiological evaluation)

 -  Stage IIIB (with malignant pleural effusion) or stage IV disease

 -  Patients with stage IIIB NSCLC without an effusion are eligible if they are not
 candidates for combined modality therapy with curative intent (i.e., radical
 chemoradiotherapy)

 -  At high risk for bevacizumab-associated hemoptysis

 -  Hemoptysis estimated as between 2.5 mL and 10 mL (largest volume of single
 episode of hemoptysis) in the past 2 months

 -  Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
 conventional techniques or ≥ 10 mm by spiral CT scan

 -  No known brain metastases by contrast-enhanced CT scan or gadolinium-enhanced MRI of
 the brain

 -  No clinical or radiologic evidence of an existing or impending spinal cord compression

 -  ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%

 -  Life expectancy > 6 months

 -  WBC ≥ 3,000/mm³

 -  Absolute neutrophil count ≥ 1,500/mm³

 -  Platelet count ≥ 100,000/mm³

 -  Bilirubin normal

 -  AST and ALT ≤ 2.5 times upper limit of normal (ULN)

 -  Creatinine normal OR creatinine clearance ≥ 50 mL/min

 -  INR < 1.5

 -  aPTT ≤ 1.5 times ULN

 -  No serious medical conditions, including any of the following:

 -  Unstable angina

 -  Myocardial infarction or stroke (cerebrovascular accident or transient ischemic
 attack) within the past 6 months

 -  Congestive heart failure

 -  Active cardiomyopathy

 -  Unstable ventricular arrhythmia

 -  Symptomatic peripheral vascular disease

 -  Active peptic ulcer disease

 -  Uncontrolled psychotic disorders

 -  Serious infections

 -  Other medical conditions potentially aggravated by treatment

 -  No social situation that would preclude study compliance

 -  No other active malignancy

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for ≥ 6 months after
 completion of study treatment

 -  No history of bleeding diathesis or coagulopathy associated with elevated risk of
 bleeding

 -  No uncontrolled hypertension (i.e., resting blood pressure consistently higher than
 systolic > 150 mm Hg and/or diastolic > 100 mm Hg with or without antihypertensive
 medication), history of labile hypertension, or history of poor compliance with
 antihypertensive medication

 -  No clinically significant proteinuria (24-hour urine protein < 1,000 mg)

 -  No serious or nonhealing wound, ulcer, or bone fracture

 -  No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
 the past 28 days

 -  No significant traumatic injury within the past 28 days

 -  No history of known allergy or reaction attributed to compounds of similar chemical or
 biological composition to bevacizumab, such as Chinese hamster ovary cell proteins or
 other recombinant human or humanized antibodies, Cremophor EL®, or other agents used
 in study treatment

 -  No pre-existing peripheral neuropathy > grade 1

 -  No prior thoracic radiotherapy

 -  At least 12 months since prior chemotherapy

 -  No prior chemotherapy for advanced disease

 -  No prior therapy with angiogenesis, vascular endothelial growth factor (VEGF), or
 VEGF-receptor inhibitors

 -  Cyclooxygenase-2 inhibitors as a noncancer therapy allowed

 -  At least 28 days since prior and no concurrent major surgery or open biopsy

 -  At least 12 months since prior anticancer therapy for any other malignancy except
 basal cell carcinoma of the skin, localized prostate cancer, or in situ carcinoma of
 the cervix

 -  At least 10 days since prior therapeutic anticoagulants or therapeutic thrombolytic
 agents

 -  No concurrent aspirin (> 325 mg/day) or antiplatelet agents, including dipyridamole,
 ticlopidine, clopidogrel bisulfate, or cilostazol

 -  Other concurrent nonsteroidal anti-inflammatory drugs allowed

 -  No other concurrent investigational agents

 -  No concurrent combination antiretroviral therapy for HIV-positive patients

 -  No other concurrent anticancer agents or therapies

 -  Steroids for pain, anorexia, or quality of life allowed