• Overall survival [ Designated as safety issue: No ]
  

• Response [ Designated as safety issue: No ]
  
• Duration of response [ Designated as safety issue: No ]
  
• Progression-free survival [ Designated as safety issue: No ]
  
• Toxicity [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Compare survival of patients with locally advanced or metastatic adenocarcinoma of the pancreas treated with gemcitabine with vs without bevacizumab.

Secondary

• Compare objective response rate, duration of response, and progression-free survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Correlate baseline levels of vascular endothelial growth factor (VEGF) with treatment outcome in patients treated with these regimens.
• Determine baseline and on-treatment levels of additional growth factors that may be co- or counter-regulated with VEGF and correlate these levels with response in patients treated with these regimens.
• Determine baseline and on-treatment levels of coagulation and endothelial cell activation markers that may predict thrombotic or bleeding risks in patients treated with these regimens.
• Compare the effects of these regimens on resource utilization, cost, and utilities.
• Determine estimates of marginal cost-utility.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to ECOG performance status (0-1 vs 2), disease extent (metastatic vs locally advanced), and prior radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15.
• Arm II: Patients receive gemcitabine IV as in arm I and placebo IV over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 590 patients (295 per treatment arm) will be accrued for this study within 26.8 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the pancreas

  • Locally advanced or metastatic disease
• Not amenable to curative resection
• No invasion of adjacent organs (e.g., duodenum or stomach) by CT scan
• No evidence of CNS disease, including primary brain tumor or brain metastasis

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No other significant bleeding episodes within the past 6 months

Hepatic

• Bilirubin normal
• SGOT ≤ 2.5 times upper limit of normal (ULN)
• PT and INR ≤ 1.5 times ULN (except for patients on full-dose warfarin)
• No esophageal varices

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

• No proteinuria

  • Patients with ≥ 1+ proteinuria must demonstrate < 1 g/dL of protein on 24-hour urine collection

Cardiovascular

• No clinically significant cardiovascular disease
• No uncontrolled hypertension (i.e., blood pressure > 150/90 mm Hg on medication)

• No arterial thromboembolic event within the past 6 months, including any of the following:

  • Myocardial infarction
  • Unstable angina pectoris
  • Cerebrovascular accident
  • Transient ischemic attack
• No New York Heart Association grade II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No peripheral vascular disease ≥ grade 2
• No clinically significant peripheral artery disease (i.e., claudication on < 1 block)

Pulmonary

• No hemoptysis within the past 6 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for up to 3 months after study participation
• No upper or lower gastrointestinal bleeding within the past 6 months
• No serious or non-healing wound, ulcer, or bone fracture
• No serious active viral, fungal, or bacterial infection
• No infection requiring parenteral antibiotics
• No hypersensitivity to Chinese hamster ovary cell products or other recombinant antibodies
• No significant traumatic injury within the past 28 days
• No other active malignancy except nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bevacizumab in the adjuvant or metastatic setting
• No other prior vascular endothelial growth factor inhibitors
• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
• No concurrent pegfilgrastim

Chemotherapy

• See Radiotherapy

• More than 4 weeks since prior adjuvant chemotherapy and recovered

  • Patients must have evidence of disease progression after adjuvant chemotherapy
• No prior chemotherapy for metastatic disease
• No prior gemcitabine in the adjuvant or metastatic setting
• No other concurrent chemotherapy agents

Endocrine therapy

• No concurrent hormones except steroids for adrenal failure, hormones for non-disease-related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic

Radiotherapy

• Prior radiotherapy with or without a radiosensitizing dose of fluoropyrimidines allowed provided there is disease outside radiotherapy port
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent palliative radiotherapy

Surgery

• More than 28 days since prior major surgical procedure or open biopsy
• More than 7 days since prior fine needle aspirations
• No concurrent major surgical procedures

Other

• More than 1 month since prior thrombolytic agent
• No concurrent thrombolytic agent
• Concurrent full-dose anticoagulants allowed provided the patient is maintained on a stable dose of warfarin with an in-range INR (between approximately 2-3) OR on a stable dose of low molecular weight heparin