Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- To compare the overall survival (OS) of patients with advanced non-squamous non-small
cell lung cancer (NSCLC) treated with maintenance therapy with bevacizumab vs pemetrexed
disodium vs bevacizumab and pemetrexed disodium following induction therapy.

Secondary

- To determine the response rate in patients treated with these regimens.

- To evaluate the progression-free survival (PFS) of patients treated with these regimens.

- To define the toxicity of these regimens in these patients.

- To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA,
and ERCC-118 TT in patients treated with induction therapy comprising paclitaxel,
carboplatin and bevacizumab and determine the association between genotypes and response
rate.

- To determine the association between bevacizumab and pemetrexed disodium population
pharmacokinetics and patient-specific covariate with bevacizumab or pemetrexed disodium
toxicity.

- To determine the frequency of TSER*3 polymorphisms in NSCLC and the association between
TSER polymorphisms and benefit from pemetrexed disodium.

- To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations in existing tumor
specimens as a predictor of pemetrexed disodium response.

- To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 collectively or
monogenically as markers for variation in efficacious and/or toxic response of
individuals to treatment with taxanes.

- To explore the association between proteomic profiles and ICAM, VEGF, and FGF-beta with
the clinical outcomes of the study (OS, PFS, and response) (Closed as of 04/01/2010).

- To evaluate the ability of FOX03a to predict first-line treatment outcome in
non-squamous NSCLC.(Closed as of 04/01/2010)

- To evaluate the ability of ADSS1 to predict outcome of pemetrexed maintenance treatment
in non-squamous NSCLC.(Closed as of 04/01/2010)

- To develop proteomic classifiers to identify patient populations that would benefit from
bevacizumab or pemetrexed therapy.(Closed as of 04/01/2010)

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to gender
(male vs female), stage of disease (IIIB-T4Nx [with nodule in ipsilateral lung lobe and not
candidate for combined chemotherapy and radiation] and IV M1a vs IV M1b vs recurrent), best
response to first-time therapy (complete response/partial response vs stable disease), and
smoking status (never vs smoker).

- Induction therapy: Patients receive paclitaxel IV over 3 hours, carboplatin IV over
15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21
days for 4 courses in the absence of disease progression or unacceptable toxicity.

- Maintenance Therapy: Patients achieving complete response, partial response or stable
disease following induction therapy are randomized to 1 of 3 treatment arms. Treatment
begins within 6 weeks of the last day of induction chemotherapy administration.

- Arm I: Patients receive bevacizumab IV over 30-90 minutes on day 1.

- Arm II: Patients receive pemetrexed disodium IV over 10 minutes on day 1.

- Arm III: Patients receive bevacizumab as in arm I and pemetrexed as in arm II. In
all arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetics, protein biomarkers, proteomic profiling (closed as of 04/01/10), and other
analyses.

After completion of study therapy, patients are followed up every 3 months for 2 years and
then every 6 months for 2-5 years.

DISEASE CHARACTERISTICS:

- Cytologically or histologically confirmed non-small cell lung cancer (NSCLC)

- Predominant non-squamous histology

- NSCLC not otherwise specified allowed

- Mixed tumors are categorized by the predominant cell type

- Must meet 1 of the following criteria:

- Stage IV disease including M1a or M1b stages or recurrent disease

- Stage IIIB (T4NX) disease with ipsilateral lung lobe allowed provided patients
are not candidates for combined chemotherapy or radiotherapy

- Measurable or non-measurable disease as defined by RECIST criteria

- Patient must have an overall stable or better response after 4 courses of induction
therapy

- No cavitary lesions in the lungs

- Patients with brain metastasis must have received local therapy to the brain and have
no evidence of progression in the brain for at least 2 weeks from the time of
completion of local therapy, prior to registration

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Leukocytes ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Total bilirubin ≤ institutional upper limit of normal (ULN)

- AST and ALT ≤ 3 times ULN

- Creatinine ≤ institutional ULN OR creatinine clearance ≥ 60 mL/min

- Urine protein:urine dipstick ≤ 0-1+ (if > 1+, urine protein creatinine ratio must be <
1)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must agree to abstain from sexual intercourse or to use adequate
contraceptive methods during and for at least 6 months after completion of study
therapy

- No prior malignancy within the past 3 years except superficial melanoma, basal cell
carcinoma, or carcinoma in situ

- No major hemoptysis within the past 4 weeks

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Serious cardiac arrhythmia

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- Patients with hypertension must be adequately controlled (BP < 150/100 mm Hg) with
appropriate anti-hypertensive therapy or diet

- No history of arterial thrombotic events or major bleeding within the past 12 months

- No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within the past 6 months

- No significant traumatic injury in the past 3 months

- No clinically significant cardiovascular disease

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 6 months

- No history of serious non-healing wounds, ulcers, or bone fractures

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 12 months since prior adjuvant chemotherapy

- At least 2 weeks since prior radiotherapy

- Patients must not have had any major surgery such as thoracotomy, laparotomy,
craniotomy, or significant traumatic injury within 6 weeks prior to registration

- Biopsy procedures and chest tube insertion are not considered major surgery for
the purpose of this protocol

- More than 7 days since a core biopsy

- Concurrent therapeutic anti-coagulation allowed

- No prior systemic chemotherapy for advanced stage lung cancer

- No prior paclitaxel, pemetrexed disodium, or bevacizumab

- Prior carboplatin allowed provided it was given as part of adjuvant chemotherapy

- No concurrent anti-retroviral therapy in patients with HIV infection