| Exclusion Criteria: | 1) Squamous cell carcinoma, except for patients with no intrathoracic disease or small peripheral lesions only A peripheral lung lesion was defined as any lesion meeting the following criteria: A lesion (or lesions) in which the epicenter of the tumor is </= 2 cm from the costal of diaphragmatic pleura in a 3-dimensional orientation based on each lobe of the lung, and > 2 cm from the trachea, main, and lobar bronchi.
2) Adenopathy was not considered when assessing the peripheral nature of a patient's squamous cell carcinoma. Patients were eligible for study participation irrespective of the proximity of their adenopathy to the costal or diaphragmatic pleura or major airways.
3) Prior treatment with an investigational or marketed inhibitor of the EGFR pathway or anti-angiogenesis agent. Angiogenesis inhibitors include (but are not limited to) bevacizumab, thalidomide, CP 547632, SU 11248, and PTK 787.
4) Systemic chemotherapy, radiotherapy, or investigational treatment within 28 days prior to randomization
5) Local palliative radiotherapy within 14 days prior to randomization or persistent adverse effects from radiotherapy that have not resolved to Grade 2 or less following completion of treatment
6) Whole brain radiotherapy or stereotactic radiosurgery for brain metastases within 4 weeks of Day 0
7) Neurosurgery for brain metastases within 24 weeks of Day 0.
8) Brain biopsy within 12 weeks of Day 0
9) Current use of dexamethasone for treatment associated with brain metastases
10) History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or 2.5 mL per episode) within 3 months prior to randomization unless definitively treated with surgery or radiation
11) History of any of the following within 6 months prior to day 0: serious systemic disease, including myocardial infarction, uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg taken per the JNC 7 guidelines [see http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm]), unstable angina, New York Heart Association (NYHA) Grade 2 or greater CHF, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible)...continued in ex #12
12) Continuation from exclusion # 11: clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess. Patients with evidence of hypertension during study screening were to be evaluated for uncontrolled hypertension in accordance with the JNC guidelines.
13) Evidence of bleeding diathesis or coagulopathy or other serious or acute internal bleeding within 6 months prior to randomization
14) CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months
15) Progressive neurologic symptoms in patients with a history of brain metastases
16) Full-dose anticoagulation with warfarin: Patients who require full-dose anticoagulation may be treated with low-molecular-weight heparin or fondaparinux. Patients fully anticoagulated with warfarin during the study will be discontinued from bevacizumab/placebo.
17) Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) In addition, patients who require treatment with full-dose anticoagulants for any reason during the course of the study will be discontinued from bevacizumab/placebo. Those patients remaining on Tarceva who require full-dose anticoagulation with warfarin will need continued close INR monitoring.
18) Chronic daily use of aspirin (> 325 mg/day) or other full-dose NSAIDS with anti-platelet activity. Treatment with other antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, and /or cilostazol) was permitted.
19) In-patient surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization (placement of a central line is not considered surgery, and can be placed on the same day as study drug administration)
20) Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior to randomization
21) Anticipation of need for a major surgical procedure during the course of the study
22) Serious, non-healing wound, ulcer, or bone fracture
23) Inability to take oral medication or requirement for IV alimentation or total parenteral nutrition with lipids, or prior surgical procedures affecting absorption
24) Any of the following abnormal hematologic values (within 1 week prior to randomization) ANC </= 1000 cells/microliter Platelet count </= 100,000 cells/microliter Hemoglobin </= 9.0 g/dL INR >/= 1.5 x upper limit of normal (ULN)
25) Any of the following abnormal liver function tests (within 1 week prior to randomization) Serum bilirubin >/=1.5 x ULN Albumin </= 2.5 g/dL Serum ALT >/= 2 x ULN (unless clearly due to liver metastases, then 5 x ULN) Serum AST >/=2 x ULN (unless clearly due to liver metastases, then 5 x ULN)
26) Other baseline laboratory values Uncontrolled hypercalcemia (>/=11.5 mg/dL) Urinary protein to creatinine ratio >/= 1 (spot urine) or serum creatinine >/= 2.0 x ULN
27) Pregnancy or breast-feeding Because of the possible teratogenic effect, pregnant women and women who are currently breast-feeding may not participate in this study. All women of childbearing potential must have a negative pregnancy test within 1 week prior to randomization
28) Presence of another invasive cancer within 5 years prior to randomization, except for adequately treated basal or squamous cell skin cancer, or carcinoma in situ of the cervix
29) Evidence of confusion or disorientation, or history of major psychiatric illness that may impair the patient's understanding of the Informed Consent Form or their ability to comply with study requirements |