Chemotherapy With or Without Bevacizumab in Patients With Completely Resected Stage IB-IIIA Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate overall survival with chemotherapy with or without bevacizumab used in the
adjuvant setting in patients with resected stage IB (>= 4 cm) - IIIA non-small cell lung
cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To evaluate disease-free survival and toxicity with chemotherapy with or without
bevacizumab used in the adjuvant setting in patients with resected stage IB (>= 4 cm) - IIIA
NSCLC.

CORRELATIVE STUDIES:

I. To perform analyses of tissue and blood to establish factors that predict clinical outcome
in patients receiving chemotherapy, with or without bevacizumab, for resected early stage
NSCLC.

II. To determine whether smoking status is linked to outcome for patients with resected stage
IB (>= 4 cm) - IIIA NSCLC treated with chemotherapy with or without bevacizumab in the
adjuvant setting.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (adjuvant chemotherapy without bevacizumab): Patients receive 1 of 4 chemotherapy
regimens.

REGIMEN 1: Patients receive vinorelbine ditartrate intravenously (IV) over 10 minutes on days
1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following vinorelbine
ditartrate administration.

REGIMEN 2: Patients receive docetaxel IV over 1 hour on day 1 and cisplatin over 1 hour on
day 1 immediately following docetaxel administration.

REGIMEN 3: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and
cisplatin IV over 60 minutes on day 1 immediately following gemcitabine administration.

REGIMEN 4 (non-squamous histology only): Patients receive pemetrexed disodium IV over 10
minutes and cisplatin IV over 1 hour on day 1 immediately following pemetrexed disodium
administration.

In all regimens, treatment repeats every 21 days for up to 4 courses in the absence of
disease progression or unacceptable toxicity.

ARM II (adjuvant chemotherapy with bevacizumab): Patients receive chemotherapy as in Arm I.
Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab
repeats every 21 days for up to 1 year.

After completion of study treatment, patients are followed up periodically for 10 years.

Inclusion Criteria:

- In order to be eligible for this trial, patients must have undergone complete
resection of their non-small cell lung cancer (NSCLC) [stage IB (>= 4 cm)] - [IIIA
(T2-3N0, T1-3N1, T1-3N2] prior to enrollment; accepted types of resection will consist
of lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy; resections by
segmentectomy or wedge resection will not be accepted; mediastinal lymph node sampling
at specified levels is required pre-operatively (mediastinoscopy) or intraoperatively
(level 7 and 4 for right sided tumors or level 7 and 5 and/or 6 for left sided tumors)

- Patients must be no less than 6 weeks (42 days) and no more than 12 weeks (84 days)
post-thoracotomy at the time of randomization and must be adequately recovered from
surgery

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Absolute neutrophil count (ANC) >= 1500 mm^3

- Platelets >= 100,000/mm^3

- Prothrombin time/international normalized ratio (INR) =< 1.5

- Or, if patient is on therapeutic anticoagulation, prothrombin time/INR =< 3.0

- Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if
patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN

- Total bilirubin =< 1.5 mg/dL

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5
x upper limit of normal (ULN)

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x
upper limit of normal (ULN)

- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN)

- Urine protein should be screened by urine analysis for urine protein creatinine (UPC)
ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must
be < 1000 mg (1 g) for patient enrollment

- Patients with a known history of myocardial infarction or other evidence of arterial
thrombotic disease (angina) will be allowed on study only if they have had no evidence
of active disease for at least 12 months prior to randomization

- Both fertile men and women must agree to use adequate contraceptive measures during
study treatment and for at least 6 months after completion of bevacizumab

- All patients must have a documented blood pressure (BP) with systolic =< 150 and
diastolic =< 90 within 28 days of registration; patients with known hypertension must
be on a stable regimen of anti-hypertensive therapy

- Patients receiving daily treatment with aspirin or non-steroidal anti-inflammatory
agents (NSAIDS) are eligible

- Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving
prophylactic anticoagulation of venous access devices, provided that coagulation
studies meet other entry criteria above; caution must be exercised for patients
requiring anticoagulation, including treatment with low dose heparin or low molecular
weight heparin for deep vein thrombosis (DVT) prophylaxis while on study

- Patients with pre-operative hemoptysis that has resolved post-operatively are eligible

- Patients who will receive pemetrexed (pemetrexed disodium)/cisplatin therapy must also
meet the following criteria:

- Calculated creatinine clearance must be obtained within 2 weeks of randomization
and calculated creatinine clearance (CrCl) must be >= 45 mL/min using the
standard Cockcroft and Gault formula, or the measured glomerular filtration rate
(GFR) using the appropriate radiolabeled method ([51]chromium-labeled
ethylenediaminetetraacetic acid [51-CrEDTA] or technetium 99m
diethylenetriamine-pentaacetic acid [Tc99m-DTPA]) must be used to calculate CrCl

Exclusion Criteria:

- Any history of cancer within 5 years from randomization, with the exception of in-situ
carcinoma of the cervix or completely resected non-melanoma skin cancer

- Having received any of the following:

- Prior systemic chemotherapy at any time, but methotrexate (MTX) given in low
doses for non-malignant conditions with last dose at least 2 weeks prior to date
of registration will be allowed and other low dose chemotherapeutics for
non-malignant conditions will be considered, but review by the study chair is
required

- Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5
years of randomization; (prior surgery, biologic therapy, hormonal therapy, or
radiation therapy for a malignancy over 5 years prior to enrollment that is now
considered cured is acceptable)

- Any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA)

- Women who are pregnant or breast-feeding

- All females of childbearing potential must have a blood or urine test within 2
weeks prior to randomization to rule out pregnancy

- Any clinically significant ongoing, active or serious infection, symptomatic or
uncontrolled congestive heart failure, symptomatic or uncontrolled cardiac arrhythmia
or any other medical condition or psychiatric illness/social situations that would
limit compliance with study requirements

- History of bleeding diathesis or coagulopathy

- Treatment with dipyridamole (Persantine), ticlopine (Ticlid), clopidogrel (Plavix)
and/or cilostazol (Pletal); patients must have stopped taking any of these agents at
least 7 days prior to randomization

- Serious non-healing wound, ulcer, bone fracture, or having undergone a major surgical
procedure, open biopsy, or significant traumatic injury within 28 days prior to
randomization OR core biopsy within 7 days prior to randomization

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days prior to randomization

- Any anticipated major surgical procedure(s) during the course of the study

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- Ongoing post-operative hemoptysis (defined as bright red blood of 1/2 teaspoon or
more)

- Squamous cell histology for patients who will receive pemetrexed (pemetrexed
disodium)/cisplatin therapy