Bevacizumab and Interleukin-2 in Treating Patients With Metastatic Kidney Cancer

OBJECTIVES:

Primary

- Estimate the response, progression-free survival, and overall survival of patients with
metastatic renal cell carcinoma (RCC) treated with bevacizumab and high-dose
interleukin-2 (IL-2).

Secondary

- Compare the response and survival of patients with metastatic RCC treated with
bevacizumab and high-dose IL-2 with the historical data of patients treated with
high-dose IL-2 alone.

- Compare the toxicity of bevacizumab and high-dose IL-2 in patients with metastatic RCC
with the historical data of patients treated with high-dose IL-2 alone, in terms of
number of doses of IL-2 administered during the first course of therapy, toxicity after
the scheduled ninth dose of IL-2, and frequency of grade III and IV or unexpected or
rare toxicities.

- Compare the time to disease progression in patients with metastatic RCC treated with
bevacizumab and high-dose IL-2 with the historical data of patients treated with
high-dose IL-2 alone.

- Evaluate the pharmacokinetics and pharmacodynamics of bevacizumab and high-dose IL-2
during course 1.

- Correlate serum vascular endothelial growth factor (VEGF) levels, DC function, TCR zeta
chain expression, and arginase or arginine levels with toxicity, response, and survival
of patients treated with this regimen.

- Evaluate the utility of known prognostic criteria for RCC patients on clinical outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to prognosis (good
vs intermediate vs poor).

Patients receive bevacizumab IV over 30-90 minutes on days -13, 1, 15, 29, 43, 57, and 71
during course 1 and on days 1, 15, 29, 43, 57, and 71 during courses 2 and 3. Patients also
receive high-dose interleukin-2 every 8 hours on days 1-5 and 15-19. Treatment repeats every
84 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

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

PROJECTED ACCRUAL: A total of 65 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed metastatic renal cell carcinoma (RCC) with predominantly
clear cell histology

- Measurable disease

- No history of tumor-related hemorrhage

- No history of CNS or brain metastases

PATIENT CHARACTERISTICS:

- Karnofsky performance status ≥ 80%

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL (transfusion or recombinant erythropoietin growth factors
allowed)

- AST ≤ 2 times upper limit of normal (ULN) (5 times ULN if due to liver metastases)

- Serum total bilirubin ≤ 2 times ULN (except for patients with Gilbert's disease)

- Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

- FEV_1 ≥ 2.0 L or ≥ 75% of predicted

- Pulmonary function testing required for patients over age 50 or with significant
pulmonary or smoking history

- No history of cerebrovascular accident or transient ischemic attacks

- No evidence of any of the following cardiac conditions*:

- Congestive heart failure

- Symptoms of coronary artery disease

- Myocardial infarction < 6 months prior to study entry

- Serious cardiac arrhythmias

- Unstable angina NOTE: *Patients > 40 years old or who have had a previous
myocardial infarction > 6 months prior to study entry are required to have a
negative or low probability cardiac stress test for cardiac ischemia

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other malignancy within the past 5 years except nonmelanoma skin cancer or
noninvasive cancer, such as cervical carcinoma in situ, superficial bladder cancer
without local recurrence, or breast cancer in situ

- Patients with a history of another invasive malignancy must be in complete
remission for ≥ 5 years

- No positive serology for HIV, hepatitis B, or hepatitis C

- No significant co-morbid illness, such as uncontrolled diabetes or active infection,
that would preclude study treatment

- No history of inflammatory bowel disease or other serious autoimmune disease

- Thyroiditis or rheumatoid arthritis allowed

- No uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg)

- Proteinuria ≤ 3+ by dipstick OR proteinuria < 2 gm by 24-hour urine collection

- Urine protein:creatinine ration < 1.0

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
6 months prior to study entry

- No significant traumatic injury within the past 28 days

- No serious, nonhealing wound, ulcer, or bone fracture

- No active bleeding

- No history of other serious hemorrhage, bleeding diathesis, or underlying
coagulopathy

- No history of deep venous thrombosis, clinically significant peripheral vascular
disease, or other thrombotic event

PRIOR CONCURRENT THERAPY:

- No organ allografts

- At least 4 weeks since prior radiotherapy or surgery and recovered

- No prior systemic therapy for metastatic RCC

- No prior bevacizumab or interleukin-2

- At least 2 weeks since prior steroids

- No major surgery or open biopsy within the past 28 days

- No minor surgical procedures, fine needle aspirations, or core biopsies within the
past 7 days, except central venous catheter placement

- No concurrent major surgery

- No concurrent corticosteroids or other immunosuppressants