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

Study Overview
=================
Brief Summary
-----------------
RATIONALE: PEG-interferon alfa-2b may interfere with the growth of tumor cells. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving PEG-interferon alfa-2b together with sorafenib may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of PEG-interferon alfa-2b and sorafenib in treating patients with unresectable or metastatic kidney cancer.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase I Study Of Peginterferon Alfa-2b (PEG-INTRON) With Sorafenib (Nexavar) In Patients With Unresectable Or Metastatic Clear Cell Renal Carcinoma (RCC).

Conditions
-----------------
Kidney Cancer

Intervention / Treatment
-----------------
* Biological: PEG-interferon alfa-2b
* Drug: Sorafenib
* Genetic: gene expression analysis
* Genetic: polymerase chain reaction
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: flow cytometry
* Other: immunoenzyme technique
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have histologically or cytologically confirmed clear cell renal cell carcinoma (RCC) 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 treatment except 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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peginterferon alfa-2b<br>Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks. | Biological: PEG-interferon alfa-2b<br>* administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.<br>* Other names: peginterferon alfa-2b;Drug: Sorafenib<br> <br> * Other names: BAY 54-9085 is the tosylate salt of BAY 43-9006;Genetic: gene expression analysis<br> <br> Genetic: polymerase chain reaction<br> <br> Genetic: reverse transcriptase-polymerase chain reaction<br> <br> Other: flow cytometry<br> <br> Other: immunoenzyme technique<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of PEG-interferon Alfa-2b and Sorafenib Tosylate |  | up to 2 months | 
| Characterize the Toxicity of Peginterferon Alfa-2b and Sorafenib in Patients With Metastatic or Unresectable Clear Cell Renal Cell Carcinoma. |  | up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival of Patients Receiving Peginterferon Alfa-2b and Sorafenib. |  | up to 1 year | 
| Response Rate of Patients Receiving Peginterferon Alfa-2b and Sorafenib. |  | up to 1 year | 
| Overall Survival |  | up to 1 year | 
| Activation of Interferon-induced Transcription Factors in Immune Cell Subsets by Flow Cytometry and Correlation of This Information With Clinical Outcome |  | up to 1 year | 
| 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 |  | Up to 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
clear cell renal cell carcinoma, stage III renal cell cancer, stage IV renal cell cancer