PEG-Interferon Alfa-2b and Sorafenib in Treating Patients With Unresectable or Metastatic Kidney Cancer

OBJECTIVES:

Primary

- To determine the maximum tolerated dose and toxicity of PEG-interferon alfa-2b and
sorafenib tosylate in patients with unresectable or metastatic clear cell renal cell
carcinoma.

Secondary

- To determine the progression-free survival of patients treated with this regimen.

- To evaluate, in a preliminary manner, the response rate and overall survival of
patients treated with this regimen.

- To evaluate the activation of interferon-induced transcription factors in immune cell
subsets (including regulatory T cells [T regs]) using a novel flow cytometric assay and
correlate this information with clinical outcome.

- To measure circulating levels of IFN-γ and IL-5 for determination of Th1/Th2 status and
CD4+, CD25+, and FoxP3 cell number (T regs) in peripheral blood.

OUTLINE: Patients receive PEG-interferon alfa-2b subcutaneously on days 1, 8, 15, 22, 29,
36, 43, and 50. Patients also receive oral sorafenib tosylate 2-3 times daily on days 15-56
of course 1 and on days 1-56 of all subsequent courses. Courses repeat every 56 days for up
to 1 year in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for correlative
laboratory studies. Peripheral blood mononuclear cells are analyzed for STAT proteins
(STAT1, STAT2, STAT3, STAT4, STAT5) and CD4+, CD25+, and FoxP3 regulatory T cells by flow
cytometric assays. Samples are also analyzed for the presence of VEGF, VEGFR, IFN-γ, and
IL-5 by ELISA assays; baseline expression of Jak-STAT signaling intermediates (Jak1, Tyk2,
IFNAR, and IRF9) by immunoblot analysis; and interferon-stimulated gene expression by real
time PCR and RT-PCR analysis.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4
months for 1 year, every 6 months for 2 years, and then annually thereafter.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed clear cell renal cell carcinoma (RCC)

- No other tumor histology other than clear cell RCC

- Tumor histology must have ≥ 50% clear cell component

- Unresectable or metastatic disease

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension and is ≥ 1.0 cm by spiral CT scan

- No prior or concurrent brain metastasis

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy > 6 months

- Good/intermediate Motzer prognostic status

- ANC ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 10.0 g/dL

- Total bilirubin ≤ 2.0 mg/dL

- AST and ALT < 2.5 times normal

- Creatinine ≤ 1.8 mg/dL OR creatinine clearance > 50 mL/min

- Calcium < 12 mg/dL (when corrected for serum albumin)

- INR < 1.5 times upper limit of normal

- Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% by 2D
echo

- Pulse oximetry ≥ 90% at rest on room air

- Not pregnant

- Negative pregnancy test

- Fertile patients must use effective contraception

- No evidence of bleeding diathesis

- No uncontrolled coagulation disorders

- No active infections requiring IV antibiotics

- No known HIV, hepatitis C, or hepatitis B

- No autoimmune disease requiring ongoing therapy

- No requirement for adrenal replacement

- No angina (controlled or uncontrolled)

- No uncontrolled hypertension

- No history of other major medical illnesses including, but not limited to, any of the
following:

- Cardiac ischemia

- Myocardial infarction

- Major cardiac arrhythmias

- Inflammatory bowel disorders

- No other prior malignancy except for previously treated basal cell or squamous cell
skin cancer, in situ cervical cancer, or other cancer for which the patient has been
disease-free for 3 years

- No significant psychiatric disease that, in the opinion of the principal
investigator, would preclude giving adequate informed consent or render immunotherapy
unsafe

PRIOR CONCURRENT THERAPY:

- No prior treatment for RCC except sunitinib malate

- Patients may have progressed or have been intolerant to sunitinib malate

- No prior systemic treatment for metastatic disease (other than sunitinib malate)

- No prior organ allografts

- At least 2 weeks since prior laparoscopic/robotic surgery

- At least 4 weeks since prior open nephrectomy

- More than 4 weeks since prior and no concurrent radiotherapy or other surgery

- More than 4 weeks since prior systemic steroids

- More than 2 weeks since prior topical, injected, or inhaled steroids

- No concurrent steroid therapy

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