Pemetrexed Disodium and Bevacizumab in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Assess the 3 month progression-free survival rate of the combination of pemetrexed
disodium with bevacizumab in a patient population with stage IIIB (due to pleural
effusion) or IV non-small cell lung cancer.

Secondary

- Determine the tumor response rate in these patients.

- Determine the effect of pemetrexed disodium in combination with bevacizumab on overall
survival and duration of response in these patients.

- Determine the toxicity profile of this drug regimen in these patients.

OUTLINE: This is an open-label, multicenter study.

Patients receive pemetrexed disodium IV over 10 minutes and bevacizumab IV over 30-90
minutes on day 1. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 5 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically diagnosed stage IIIB or IV non-small cell lung cancer

- Stage IIIB patients must have pleural effusion

- No symptomatic serosal effusion (grade 2 dyspnea) that is not amenable to
drainage

- Mixed histology allowed if all components consistent with non-small cell lung
cancer

- Tumors with squamous cell histology feature are allowed

- Must have measurable disease with at least one lesion with a longest diameter
accurately measured as ≥ 2.0 cm with conventional techniques or as ≥ 1.0 cm with
spiral CT

- Large ( > 4 cm) centrally located lesions or large lesions in close proximity to
major blood vessels should receive palliative radiation

- The irradiated lesion should not be a target lesion

- Previously treated with one chemotherapy regimen in the neoadjuvant, adjuvant, or
advanced disease setting

- No symptomatic, untreated, or uncontrolled CNS metastases

- CNS metastases treated with prior whole brain radiotherapy allowed

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/ mm^3

- Hemoglobin ≥ 9 g/dL

- Bilirubin ≤ 1.5 times upper limit of normal (ULN) or direct bilirubin normal

- AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement)

- Creatinine clearance ≥ 45 mL/min

- Urine protein:creatinine ratio < 1.0

- Pregnant or nursing women are ineligible

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after study
participation

- No seizure disorder

- No clinically significant infection

- No other second primary malignancy within the past 5 years except carcinoma in situ
of the cervix, non-melanomatous skin cancer, or low-grade (Gleason score ≤ 6)
localized prostate cancer

- No hypertension or labile hypertension

- No history of poor compliance with antihypertensive medications

- No angina pectoris

- No congestive heart failure within the past 3 months unless ejection fraction > 40%

- No myocardial infarction within the past 6 months

- No cardiac arrhythmia

- No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

- No active or recent history of hemoptysis

- Hemoptysis resolved > 2 weeks ago with measures such as palliative radiation
therapy (i.e., 3,000 cGy over 10 fractions), arteriographic embolization, or
endobronchial interventions (e.g., photodynamic therapy or brachytherapy) is
acceptable

- No diabetes

- No prior serious, non-healing wounds, ulcers, or bone fractures

- No history of stroke within the past 6 months

- No history of abdominal fistula or gastrointestinal perforation

- No intra-abdominal abscess within the past 6 months

- Not at greater than average risk of bleeding

- No significant traumatic injury within the past 4 weeks

PRIOR CONCURRENT THERAPY:

- No aspirin at doses ≥ 1.3 grams per day within 10 days prior to or 10 days after
pemetrexed disodium treatment

- No chemotherapy within the past 3 weeks (6 weeks for mitomycin C or nitrosoureas)

- No immunotherapy or biologic therapy within the past 2 weeks

- No full field radiation therapy within the past 4 weeks or limited field radiation
therapy within the past 2 weeks

- The site of previous radiotherapy should have evidence of progressive disease if
it is the only site of disease

- No prior post pelvic radiation

- No prior use of pemetrexed disodium

- No prior radiation to > 25% of the marrow cavity

- No major surgery (i.e., laparotomy) or open biopsy within the past 4 weeks

- No minor surgery within the past 2 weeks except insertion of a vascular access device

- No concurrent major surgery

- No other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or any
ancillary therapy considered investigational within the past 4 weeks

- No concurrent use of Hypericum perforatum (St. John's wort)

- No concurrent anticoagulant use

- Low-dose warfarin or heparin for deep venous thrombosis prophylaxis allowed