Sorafenib in Treating Patients Undergoing Surgery for Stage II, Stage III, or Stage IV Kidney Cancer

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving sorafenib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This clinical trial is studying the side effects and how well sorafenib works in treating patients undergoing surgery for stage II, stage III, or stage IV kidney cancer.

Detailed Description
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OBJECTIVES: Primary Determine the safety and feasibility of systemic sorafenib tosylate therapy when given prior to definitive nephrectomy in patients with stage II-IV renal cell carcinoma (RCC). Secondary Determine all levels of response in primary renal tumors of patients treated with this drug. Assess effects of this drug on gene expression, protein expression, and metabolic profile using tumor tissue samples from these patients. Identify biomarkers or biomarker patterns associated with RCC or this drug in these patients. OUTLINE: This is a pilot, open-label, nonrandomized study. Patients receive oral sorafenib tosylate twice daily for 4-8 weeks in the absence of disease progression or unacceptable toxicity. After completion of neoadjuvant therapy, patients undergo surgical resection of their kidney tumor. Patients undergo blood and urine sample collection at baseline and after completion of treatment (i.e., at 4 and 8* weeks) for VEGF analysis. Samples are examined by enzyme-linked immunosorbent assay for measurement of serum and urinary VEGF levels. NOTE: *Blood sampling at 8 weeks is only for those patients undergoing 8 weeks of study therapy. Patients also undergo tissue sample collection at the time of nephrectomy. Tissue samples are examined by microarray analysis and IHC staining for expression of CD31/PECAM, HIF1α, and HIF2α. Immunohistochemical staining to identify biomarkers of microvessel density is also performed. Tissue samples are also examined for gene expression and metabolic profile by small molecule mass spectroscopy, as well as VHL gene mutation by VHL mutation analysis. Patients are followed at 4-8 weeks after nephrectomy.

Official Title
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A Pilot Neoadjuvant Clinical Trial With Evaluation of Molecular Effects With Sorafenib Tosylate for Patients With Stage II or Greater Renal Cell Carcinoma

Conditions
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Kidney Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of renal cell carcinoma (RCC) as confirmed by either of the following: Radiographic documentation by MRI or CT scan Histological evidence of primary RCC Stage II-IV disease, as defined by any of the following: T > 7 cm Renal vein involvement Local invasion Evidence of lymph node involvement Distant metastatic disease Deemed suitable for nephrectomy by a urologist No requirement for surgery earlier than 4 weeks from study entry No known brain metastasis Patients with neurological symptoms must undergo a CT scan or brain MRI to exclude brain metastasis PATIENT CHARACTERISTICS: ECOG performance status 0-1 Hemoglobin ≥ 9.0 g/dL ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement) Creatinine ≤ 2.5 times ULN or glomerular filtration rate ≥ 50 mL/min INR ≤ 1.5 AND PTT normal Stable INR required at baseline for patients on warfarin Not pregnant or nursing Negative pregnancy test Fertile women must use effective contraception Fertile men must use effective contraception during and for ≥ 2 months after the last dose of sorafenib tosylate No other active primary malignancy except skin cancer No active coronary artery disease No active bleeding diathesis Closely monitored therapeutic anticoagulation allowed No cardiac disease, including any of the following: New York Heart Association class III-IV congestive heart failure Unstable angina (i.e., anginal symptoms at rest) or new onset angina (i.e., beginning within the past 3 months) Myocardial infarction within the past 6 months No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management No known HIV infection or chronic hepatitis B or C No active, clinically serious infection > grade 2 No thrombolic or embolic events, such as a cerebrovascular accident or transient ischemic attacks, within the past 6 months No pulmonary hemorrhage or bleeding event ≥ grade 2 within the past 4 weeks (≥ grade 3 for any nonpulmonary hemorrhage or bleeding event) No serious nonhealing wound, ulcer, or bone fracture No significant traumatic injury within the past 4 weeks No known or suspected allergy to sorafenib tosylate or any agent given in the course of this study No condition that impairs the patient's ability to swallow whole pills No malabsorption problem PRIOR CONCURRENT THERAPY: No major surgery or open biopsy within the past 4 weeks Concurrent anticoagulation therapy (e.g., warfarin or heparin) allowed No other concurrent investigational or commercial agents or therapies for RCC No concurrent Hypericum perforatum (St. John's wort) or rifampin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm Study<br> | Drug: sorafenib tosylate<br>* Patients will receive treatment with 400mg of sorafenib, orally, twice daily, on a continuous basis as a single agent for at least 4 weeks, but not more than 8 weeks prior to their scheduled nephrectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects experiencing adverse events while taking sorafenib prior to nephrectomy | Adverse events will be assessed (graded) using CTCAE criteria | 8 weeks | 
| Feasibility of neoadjuvant systemic therapy prior to nephrectomy | Feasibility will be measured by the proportion of patients who complete therapy | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response in primary renal tumors | All patients will undergo pre and post-treatment tumor imaging by CT or MRI. Measurement of the primary tumor, and up to three largest index lesions for patients with metastatic disease, will be recorded on the case report form. The overall percentage of change in the sum of greatest dimension(s) of the kidney lesion (and three largest index lesions, if any) will be recorded. Response to therapy will be measured in absolute size change, as well as according to traditional RECIST criteria. | 8 weeks | 
| Effects of sorafenib tosylate therapy on gene expression, protein expression, and metabolic profile | Microarray data will be done using statistical analysis and hierarchical clustering with the assistance of the UNC Genomics and Bioinformatics Core Facility | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II renal cell cancer, stage III renal cell cancer, stage IV renal cell cancer