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

OBJECTIVES:

Primary

- Determine the efficacy of pemetrexed disodium, gemcitabine hydrochloride, and
bevacizumab in chemotherapy-naïve patients with stage IIIB or IV nonsquamous cell
non-small cell lung cancer.

Secondary

- Determine the response rate in patients treated with this regimen.

- Determine the time to treatment failure in patients treated with this regimen.

- Determine the overall survival of patients treated with this regimen.

- Determine the toxicity of this regimen in these patients.

OUTLINE: Patients receive pemetrexed disodium IV over 10 minutes, gemcitabine hydrochloride
IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every
14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Patients may then receive bevacizumab alone in the absence of disease progression or
unacceptable toxicity.

After the completion of study treatment, patients are followed periodically for 6 months.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Inclusion Criteria

- Histologic or cytologic proof of non-squamous non-small cell lung cancer (NSCLC)
(adenocarcinoma, bronchioloalveolar, large cell carcinoma).

- Must have Stage IV or IIIB NSCLC. Patients with Stage IIIB must have a pleural
effusion or not be candidates for treatment for locally advanced disease with
chemoradiotherapy.

- Cannot have a tumor with cavitation..

- Have uni-dimensional measurable or evaluable disease. If disease is within a previous
radiation port there must be documented progression.

- 18 years of age and have a life expectancy of greater than 12 weeks.

- Must not have had prior chemotherapy for advanced disease.

- Must have an ECOG performance status of 0-1.

- With treated brain metastases are eligble. for details.

- Adequate organ function:

Absolute neutrophil count of > 1.5 x 109/L Platelet count > 100,000/109/L Hemoglobin >
8g/dl Calculated creatinine clearance > 45mL/min using the standard Cockroft and Gault
formula Hepatic: bilirubin < 1.5 times the upper limit of normal,alkaline phosphatase,
aspartate transaminase (AST) and alanine transaminase (ALT) < 3 times upper limit of
normal. Alkaline phosphatase, AST, ALT < 5 times upper limit of normal is acceptable if
liver has tumor involvement. Urine protein:creatinine ratio ≤1.0 at screening

- Patients of reproductive potential must use an approved contraceptive method during
and for 3 months after study.

- Must sign an informed consent that details the investigational nature of the study
according to the institutional and federal guidelines.

- Registered with the clinical trials office of the institution.

Exclusion Criteria

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

- Prior chemotherapy except for erlotinib for advanced disease.

- Uncontrolled hypertension (Blood pressure of >150/100 mmHg )

- Unstable angina

- New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
Appendix E)

- History of myocardial infarction within 6 months prior to day 1

- History of hemorrhagic or thrombotic stroke or other CNS bleed within 6 months prior
to day 1

- Clinically significant peripheral vascular disease of 61

- Evidence of bleeding diathesis or coagulopathy. Patients must not require full dose
anticoagulants for any reason.

- Known CNS disease, except for treated brain metastasis Treated brain metastases are
defined as having no evidence of progression or hemorrhage after treatment and no
ongoing requirement for dexamethasone, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, anticipation of need for major surgical procedure during the course of
the study

- Minor surgical procedures such as fine needle aspirations or core biopsies within 7
days prior to Day 0

- Urine protein:creatinine ratio > or = 1.0 at screening

- History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess
within 6 months prior to Day 0

- Serious, non-healing wound, ulcer, or bone fracture

- Evidence of cavitation in the tumor.

- Intrathoracic lung carcinoma of squamous cell histology Mixed tumors will be
categorized by the predominant cell type unless small cell elements are present, in
which case the patient is ineligible; sputum cytology alone is unacceptable.

- Extrathoracic-only squamous cell NSCLC are eligible. Patients with only peripheral
lung lesions (of any NSCLC histology) will also be eligible.

- History of hemoptysis (bright red blood of 1/2 teaspoon or more within 28 days of
registration or clinical history of > Grade 2

- Clinically significant effusions that cannot be drained

- Inability to comply with study and/or follow-up procedures

- Previous or concurrent malignancies with the exception of adequately treated squamous
cell or basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any
other malignancy treated and in clinical remission for more than 3 years.

- Prior radiation therapy to the target lesion, unless the lesion is clearly progressing
and the interval between the most recent radiation therapy and enrollment is at least
4 weeks.

- Pregnancy or lactating females. All pre-menopausal women should have a negative urine
pregnancy test prior to enrollment. All patients of reproductive potential should
agree to use an effective contraceptive method.

- Serious concomitant systemic disorders (including oncologic emergencies) incompatible
with the study (at the discretion of the investigator).

- Inability to interrupt non-steroidal anti-inflammatory agents 2 days before, the day
of, and 2 days after the dose of pemetrexed.

- Disease which cannot be radiologically imaged.

- Inability to take dexamethasone, folic acid or vitamin B12 administration.