Erlotinib Hydrochloride With or Without Bevacizumab in Treating Patients With Stage IV Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutations

PRIMARY OBJECTIVES:

I. To determine the progression-free survival of erlotinib (erlotinib hydrochloride) and
bevacizumab versus that of erlotinib alone for the purpose of deciding if the combination arm
is worth pursuing in a phase III trial.

SECONDARY OBJECTIVES:

I. To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone.

II. To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone.

III. To investigate the progression-free survival in patients with exon deletion 19 or exon
21 L858R point mutations.

IV. To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

TERTIARY OBJECTIVES:

I. To correlate EGFR mutations detected in plasma deoxyribonucleic acid (DNA) with those
detected in tumor DNA.

II. To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor
biopsies using more sensitive mutation detection methods.

III. To investigate progression free survival of EGFR mutant NSCLC patients with and without
concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific
quantitative polymerase chain reaction (PCR).

IV. To prospectively evaluate the predictive value of plasma VEGF-A levels on progression
free survival in patients treated with erlotinib alone or in combination with bevacizumab.

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

ARM A: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21.

ARM B: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab intravenously
(IV) over 30-90 minutes on day 1.

In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 6 years.

Inclusion Criteria:

- Histologic documentation of primary lung carcinoma, non-squamous histology with
activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R
mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory
Improvement Amendments (CLIA) certified lab; either institutional or through a
commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report
from the commercial laboratories report the specific mutations detected, and the
method of detecting the exon 19 and exon 21 L858R point mutations must be available

- Stage IV disease according to the 7th Edition of the American Joint Committee on
Cancer staging system

- Measurable disease

- Life expectancy of >= 12 months

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

- Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to
randomization

- Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization

- Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization

- Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to
randomization

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or
bone metastases obtained =< 14 days prior to randomization

- Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x
ULN obtained =< 14 days prior to randomization

- Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0
obtained =< 14 days prior to randomization

- Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at
baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of
protein in 24 hours

- Negative pregnancy test done =< 7 days prior to randomization, for women of
childbearing potential only

- Provide informed written consent

- Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling
institution for follow-up

- Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

- Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a
predominant squamous component

- Prior chemotherapy or treatment for metastatic non-small cell lung cancer

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive, per
medical doctor (MD) discretion

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations, or any other medical condition
that would limit compliance with study requirements

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic
skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior
malignancy, they must not be receiving other specific treatment (i.e. hormonal
therapy) for their cancer

- History of myocardial infarction or other evidence of arterial thrombotic disease
(angina), symptomatic congestive heart failure (New York Heart Association >= grade
2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has
no evidence of active disease for at least 6 months prior to randomization

- History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) =< 6
months prior to randomization

- History of bleeding diathesis or coagulopathy

- Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or
diastolic pressure > 100 mmHg on anti-hypertensive medications); Note: history of
hypertensive crisis or hypertensive encephalopathy not allowed

- Current or recent (=< 10 days prior to randomization) use of aspirin (> 325 mg/day),
clopidogrel (> 75 mg/day), or prasugrel (> 10 mg/day)

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

- History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess
=< 6 months prior to randomization

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

- History of hemoptysis >= grade 2 (defined as bright red blood of at least 2.5 mL) =< 3
months prior to randomization

- Known central nervous system (CNS) disease, except for treated brain metastasis; Note:
treatment for brain metastases may include whole brain radiotherapy (WBRT),
radiosurgery (RS); gamma knife, linear accelerator (LINAC), or equivalent or a
combination as deemed appropriate by the treating physician; patients with CNS
metastases treated by neurosurgical resection or brain biopsy performed =< 3 months
prior to randomization will be excluded; Note: craniotomy or intracranial biopsy site
must be adequately healed, free of drainage or cellulitis, and the underlying
cranioplasty must appear intact at the time of randomization; study treatment should
be initiated > 28 days following the last surgical procedure (including biopsy,
surgical resection, wound revision, or any other major surgery involving entry into a
body cavity)

- Significant vascular disease (e.g. aortic aneurysm surgical repair or recent
peripheral arterial thrombosis) =< 6 months prior to randomization

- Radiotherapy to any site for any reason =< 14 days prior to randomization

- Receiving any medications or substances that are strong or moderate inhibitors of
CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days
prior to randomization:

- Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept),
atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL),
itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir
(Fortovase, Invirase), telithromycin (Ketek)

- Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin,
E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice,
verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM),
diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor
XR, Diltia XT, Taztia XT, Tiazac)

- Receiving any medications or substances that are strong or moderate inducers of
CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization:
efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro,
Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin
(Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin),
St. John?s wort