Sorafenib in Treating Patients With Locally Advanced or Metastatic 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 how well sorafenib works in treating patients with locally advanced or metastatic kidney cancer.

Detailed Description
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OBJECTIVES: Primary To demonstrate the feasibility and safety of sorafenib tosylate when given prior to nephrectomy or metastasectomy. To evaluate the ability of diffusion-weighted magnetic resonance imaging (DW-MRI) to detect early and ongoing microstructural changes in primary and metastatic renal cell carcinoma lesions during neoadjuvant therapy with sorafenib tosylate. To correlate early and ongoing microstructural changes in primary and metastatic renal cell carcinoma lesions with pathologic and clinical findings at the time of nephrectomy or metastasectomy. To evaluate the ability of changes in DW-MRI to predict subsequent favorable response to treatment (complete or partial response or stable disease) after 4 weeks of therapy. OUTLINE: Patients receive oral sorafenib tosylate twice daily on days 1-28. Patients then undergo a nephrectomy or metastasectomy in week 5. Patients with residual metastatic disease may continue sorafenib tosylate twice daily and undergo a diffusion-weighted MRI (DW-MRI) every 8 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo a DW-MRI of the abdomen and pelvis at baseline and prior to week 5 to evaluate microstructure tumor changes and to allow for prediction of sorafenib tosylate benefit. DW-MRI results are correlated with surgical and pathologic findings obtained at week 5. Resected tumor tissue are analyzed for vascular density and to distinguish apoptotic cell death from necrotic cell death via immunohistochemistry and to measure apoptotic cell death via TUNEL assay. After completion of study treatment, patients are followed every 3 months for 2 years.

Official Title
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Correlation of Pathologic Findings After Neo-adjuvant Sorafenib With Results of Diffusion-Weighted Magnetic Resonance Imaging in Patients With Locally Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Conditions
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Hereditary Clear Cell Renal Cell Carcinoma, Kidney Cancer

Intervention / Treatment
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* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed newly diagnosed clear cell renal cell carcinoma, meeting 1 of the following criteria: Localized disease, as evidenced by intact, bulky, and primary renal lesions (T1 > 3 cm, any T2, T3, or T4) appropriate for nephrectomy Limited metastatic disease, as evidenced by any renal primary (T1 > 3 cm, any T2, T3, or T4) appropriate for cytoreductive nephrectomy Isolated abdominal/pelvic recurrence with limited metastatic burden (minimum size > 2 cm) appropriate for metastasectomy No known brain metastasis Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group performance status 0-1 Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alanine aminotransferase and Aspartate aminotransferase ≤ 2.5 times ULN (≤ 5 times ULN with liver involvement) Creatinine ≤ 1.5 times ULN Estimated glomerular filtration rate > 30 mL/min (for patients receiving Gd-enhanced MRI) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to, during (men and women), and for at least 3 months after (men) completion of study therapy Adequate cardiac and pulmonary status for operative therapy No active clinically serious infection > CTCAE grade 2 No known HIV, hepatitis B, or hepatitis C infections No serious non-healing wound, ulcer, or bone fracture No significant traumatic injury within the past 4 weeks No pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within the past 4 weeks No other hemorrhage/bleeding event ≥ CTCAE grade 3 within the past 4 weeks No history of an uncontrolled bleeding disorder including, but not limited to, any of the following: Bleeding diathesis Coagulopathy No cardiac disease or condition including, but not limited to, any of the following: New York Heart Association class II-IV congestive heart failure Unstable angina (anginal symptoms at rest) New onset angina beginning within the last 3 months Myocardial infarction within the past 6 months Cardiac ventricular arrhythmias requiring antiarrhythmic therapy No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical management No thrombolic or embolic events within the past 6 months (e.g., cerebrovascular accident including transient ischemic attacks) No condition that impairs the ability to swallow whole pills No malabsorption problem No contraindication to MRI, including, but not limited to, any of the following: Ferromagnetic implants Dental work Pacemakers Metallic implants Severe claustrophobia which precludes closed MRI testing No known or suspected allergy to sorafenib tosylate No contraindication or allergy to gadolinium (e.g., end stage renal disease requiring hemodialysis) No intercurrent illness or situation which, in the judgment of the investigator, would affect assessments of clinical status and study endpoints significantly PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior major surgery or open biopsy No prior therapy with tyrosine kinase or vascular endothelial growth factor inhibitors (e.g., sunitinib malate, sorafenib, or bevacizumab) No concurrent Hypericum perforatum (St. John's wort) or rifampin No concurrent use of illicit drugs or other substances that may, in the opinion of the investigator, have a reasonable chance of contributing to toxicity or interfering with study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Experimental: Sorafenib<br>Eligible patients undergo pre-treatment DW-MRI of the abdomen and pelvis. Patient then receive Sorafenib 400mg orally twice daily on days 1-28. Following completion of 28 days of sorafenib, patients obtain a second DW-MRI. | Drug: Sorafenib<br>* 400mg by mouth twice daily for 28 consecutive days<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Difference in Apparent Diffusion Coefficient Between Baseline and Week 5 | Mean Difference in Apparent Diffusion Coefficient [Time Frame: Baseline and Week 5] To assess whether changes in the apparent diffusion coefficient (ADC) during neoadjuvant sorafenib treatment are detectable in locally advanced or metastatic kidney cancer. The ADC value will be calculated at baseline (within 28 days of initiating sorafenib) and Week 5, and the mean difference will be calculated. The percent change between this mean difference is reported. Week 5 ADC value minus baseline ADC value/divided by baseline ADC value was calculated for each participant. Apparent diffusion coefficient (ADC), obtained by measuring diffusion values at magnetic resonance imaging (MRI), is a measure of water mobility. Lower values correspond to tumor and higher values are consistent with cysts. With sorafenib therapy, the amount of free water may increase in a lesion due to necrosis, and as a result the ADC may increase in value. | Baseline and week 5 | 
| Change in Tumor Size From Baseline to Approximately 29-34 Days After Completion of Neoadjuvant Sorafenib Treatment | Tumors were measured at baseline and approximately 29-34 days after completion of neoadjuvant treatment with sorafenib (just prior to surgery). Tumors were assessed by RECIST response criteria. | Just prior to study week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clear cell renal cell carcinoma, hereditary clear cell renal cell carcinoma, recurrent renal cell cancer, stage I renal cell cancer, stage II renal cell cancer, stage III renal cell cancer, stage IV renal cell cancer