S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) in the entire study population. II. To compare
progression-free survival (PFS) by institutional review of epidermal growth factor receptor
(EGFR) fluorescent in situ hybridization (FISH)-positive patients.

SECONDARY OBJECTIVES:

I. To compare OS and PFS by centralized review in EGFR FISH-positive patients. II. To compare
PFS by centralized image review and by institutional review in the entire study population.

III. To compare the response rate (confirmed plus unconfirmed, complete and partial
responses) in a subset of patients with measurable disease in EGFR FISH-positive patient and
the entire study population.

IV. To assess the toxicities of these treatment regimens. V. To prospectively test EGFR FISH
as a predictive marker for the selection of patients for cetuximab plus chemotherapy.

III. To evaluate the role of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)
mutations in terms of cetuximab efficacy.

IV. To compare the results of EGFR FISH with KRAS mutations, EGFR mutations, EGFR
immunohistochemistry (IHC), and other purported EGFR-related biomarkers.

TERTIARY OBJECTIVES:

I. To compare PFS in patients with advanced non-small cell lung cancer (NSCLC) with an IHC
score > 200 treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or
without cetuximab.

II. To compare OS in patients with advanced NSCLC with an IHC score > 200 treated with
carboplatin, paclitaxel, and bevacizumab (if appropriate) with or without cetuximab.

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

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30
minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every
21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of 6 courses, patients receiving bevacizumab may continue to receive
bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I.
Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats
every 21 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or
without bevacizumab (as above) in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically proven primary non-small cell lung
cancer (adenocarcinoma, large cell carcinoma, squamous or unspecified); disease must
be stage IV; disease may be either newly diagnosed or recurrent after previous surgery
and/or irradiation; patients with additional lesions in an ipsilateral non-primary
lobe without M1a or M1b disease will not be considered to have stage IV disease and
are not eligible

- Patients must have a computed tomography (CT) or magnetic resonance imaging (MRI) scan
of the brain to evaluate for central nervous system (CNS) disease within 42 days prior
to registration; patient must not have brain metastases unless: (1) metastases have
been treated and have remained controlled for at least two weeks following treatment,
AND (2) patient has no residual neurological dysfunction off corticosteroids for at
least 1 day

- Patients may have measurable or non-measurable disease documented by CT or MRI; the CT
from a combined positron emission tomography (PET)/CT may be used to document only
non-measurable disease unless it is of diagnostic quality; measurable disease must be
assessed within 28 days prior to registration; pleural effusions, ascites and
laboratory parameters are not acceptable as the only evidence of disease;
non-measurable disease must be assessed within 42 days prior to registration; all
disease must be assessed and documented on the Baseline Tumor Assessment Form

- Patients must have tumor tissue available for submission that is sufficient for EGFR
FISH testing and must agree to submission of these specimens; patients must also agree
to submission of specimens for other translational medicine studies; patient must be
offered participation in banking for future research

- Patients must not have received prior chemotherapy for any stage non-small cell lung
cancer; patients must not have received prior platinum-based chemotherapy for any
purpose; patient must not have received any cetuximab, gefitinib, erlotinib, or other
investigational agents that target the EGFR pathway; patients must not have received
for any purpose prior bevacizumab or other vascular endothelial growth factor
(VEGF)-related agents; patients must not have received for any purpose prior
chimerized or murine monoclonal antibody therapy or have documented presence of human
anti-mouse antibodies (HAMA)

- Prior radiation is permitted; however, patients must have recovered from all
associated toxicities at time of registration; in order to qualify as measurable,
measurable disease must be outside the previous radiation field or must have
progressed

- Time from surgical or biopsy procedures is dependent on whether it is planned for the
patient to receive bevacizumab

- For patients who are bevacizumab-appropriate AND bevacizumab is planned: at least
28 days must have elapsed since major surgery (i.e. thoracotomy or video-assisted
thoracoscopic surgery [VATS] resection of lung cancer, open pleural biopsy or
another major surgical procedure such as abdominal surgery) or significant
traumatic injury; patients must have recovered from all associated toxicities at
the time of registration; there must be no anticipation of need for major
surgical procedures during protocol treatment; patients must not have had a core
biopsy, mediastinoscopy, pleurodesis, VATS pleural biopsy or VATS pericardial
window within 14 days prior to registration; patients must not have had a
percutaneous fine needle aspiration (FNA), thoracentesis or central venous access
device implanted within 7 days prior to registration; for other surgical
procedures not listed here, please contact the study coordinators

- For patients who are bevacizumab-inappropriate or bevacizumab is not planned: at
least 28 days must have elapsed since major surgery (i.e. thoracotomy or VATS
resection of lung cancer, open pleural biopsy or another major surgical procedure
such as abdominal surgery) or significant traumatic injury; patients must have
recovered from all associated toxicities at the time of registration; there must
be no anticipation of need for major surgical procedures during protocol
treatment; patients must not have had a core biopsy, mediastinoscopy,
pleurodesis, VATS pleural biopsy or VATS pericardial window within 7 days prior
to registration; patients must not have had a percutaneous fine needle aspiration
(FNA), or thoracentesis within 1 day prior to registration; patients may have had
a central venous access device placed at any time prior to registration; for
other surgical procedures not listed here, please contact the study coordinators

- Absolute neutrophil count (ANC) >= 1,500/mcl

- Platelet count >= 100,000/mcl

- Hemoglobin >= 9 g/dL

- Serum creatinine =< institutional upper limit of normal (IULN) AND calculated or
measured creatinine clearance >= 50 cc/min using the following Cockroft-Gault formula

- For patients who will be receiving bevacizumab, urine protein must 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 < 1,000 mg for patient
enrollment; the urine protein used to calculate the UPC ratio must be obtained within
14 days prior to registration; UPC or 24-hour protein is not required for patients who
will not receive bevacizumab Note: UPC ratio of spot urine is an estimation of the
24-hour urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour
urine protein of 1 gm

- Serum bilirubin =< 2 times IULN (for patients with liver metastases, bilirubin must be
=< 5 X IULN)

- Serum glutamic oxaloacetic transaminase (SGOT) OR serum glutamate pyruvate
transaminase (SGPT) =< 2 times IULN (for patients with liver metastases, either SGOT
or SGPT must be =< 5 X IULN)

- Zubrod performance status 0-1

- Patients must not have >= grade 2 symptomatic neuropathy-sensory (National Cancer
Institute [NCI] Common Terminology Criteria version 3.0)

- Patients must not have documented evidence of acute hepatitis or have an active or
uncontrolled infection

- Patients must not have the following: history (within past 6 months) of
cerebrovascular accident (CVA), myocardial infarction or unstable angina; or at the
time of registration, uncontrolled hypertension, New York Heart Association grade 2 or
greater congestive heart failure, serious cardiac arrhythmia requiring medication, or
clinically significant peripheral vascular disease

- Patients must have no known hypersensitivity to Chinese hamster ovary cell products or
other recombinant human antibodies (examples include trastuzumab [Herceptin] and
epoetin alpha)

- Patients must be willing to provide prior smoking history

- No other prior malignancy is allowed except for any of the following:

- Adequately treated basal cell or squamous cell skin cancer

- In situ cervical cancer

- Adequately treated stage I or II cancer from which the patient is currently in
complete remission

- Any other cancer from which the patient has been disease-free for 5 years

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system