Hereditary Clear Cell Renal Cell Carcinoma, Kidney Cancer
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGSorafenib
400mg by mouth twice daily for 28 consecutive days
Sponsors
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Difference in Apparent Diffusion Coefficient Between Baseline and Week 5 | 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. |
| Change in Tumor Size From Baseline to Approximately 29-34 Days After Completion of Neoadjuvant Sorafenib Treatment | Just prior to study week 5 | 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. |
Countries
United States
Participant flow
Recruitment details
Study was open to enrollment at Northwestern University beginning June 2008, and closed to enrollment in September 2012.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Sorafenib 400mg orally twice daily on days 1-28 | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sorafenib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Region of Enrollment United States | 9 participants |
| Renal cell carcinoma Clinical Staging T1>3cm | 0 participants |
| Renal cell carcinoma Clinical Staging T2 | 0 participants |
| Renal cell carcinoma Clinical Staging T3 | 8 participants |
| Renal cell carcinoma Clinical Staging T4 | 1 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 1 / 9 |
Outcome results
Primary
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.
Time frame: Just prior to study week 5
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib | Change in Tumor Size From Baseline to Approximately 29-34 Days After Completion of Neoadjuvant Sorafenib Treatment | -5.34 percent change |
Primary
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.
Time frame: Baseline and week 5
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sorafenib | Percentage Change in Difference in Apparent Diffusion Coefficient Between Baseline and Week 5 | -7.57 Percent change |
Post Hoc
Percentage Change of Necrosis From Baseline to Surgery
Changes in MRI will be correlated with findings of necrosis. Amount of necrosis will be measured at baseline and at time of surgery. Percentage change for necrosis will be calculated from baseline and time of surgery.
Time frame: At time of surgery
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sorafenib | Percentage Change of Necrosis From Baseline to Surgery | 20.13 Percentage change |