Brief Summary
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.
PURPOSE: This phase III trial is studying everolimus to see how well it works in treating patients with kidney cancer who have undergone surgery.
PURPOSE: This phase III trial is studying everolimus to see how well it works in treating patients with kidney cancer who have undergone surgery.
Brief Title
S0931, Everolimus in Treating Patients With Kidney Cancer Who Have Undergone Surgery
Detailed Description
OBJECTIVES:
Primary
* to compare recurrence-free survival in renal carcinoma patients randomly assigned to 54 weeks of everolimus versus 54 weeks of placebo after nephrectomy or partial nephrectomy.
Secondary
* To compare the overall survival of patients treated with everolimus vs placebo.
* To compare qualitative and quantitative toxicity between the two study arms.
* To bank tissue and biologic specimens for future study of molecular biomarkers relevant to the AKT/mTOR and other pathways implicated in the pathogenesis of renal carcinoma and to investigate their potential predictive and prognostic value.
* To bank blood specimens for the future study of the relationship between steady-state trough levels of everolimus and relevant side effects (lymphopenia, infection, hyperglycemia, hypercholesterolemia, hypertriglyceridemia) in patients treated on this study with everolimus.
OUTLINE: This is a multicenter study.
Patients are stratified according to pathologic stage (intermediate high-risk vs very high-risk), histologic subtype (clear cell vs non-clear cell), and performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.
* Arm I: Patients receive oral everolimus once daily on days 1-42. Treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral placebo once daily on days 1-42. Treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.
Archived tumor tissue, plasma, and whole blood samples may be collected periodically for biomarker analysis and other translational studies.
After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 8 years.
Primary
* to compare recurrence-free survival in renal carcinoma patients randomly assigned to 54 weeks of everolimus versus 54 weeks of placebo after nephrectomy or partial nephrectomy.
Secondary
* To compare the overall survival of patients treated with everolimus vs placebo.
* To compare qualitative and quantitative toxicity between the two study arms.
* To bank tissue and biologic specimens for future study of molecular biomarkers relevant to the AKT/mTOR and other pathways implicated in the pathogenesis of renal carcinoma and to investigate their potential predictive and prognostic value.
* To bank blood specimens for the future study of the relationship between steady-state trough levels of everolimus and relevant side effects (lymphopenia, infection, hyperglycemia, hypercholesterolemia, hypertriglyceridemia) in patients treated on this study with everolimus.
OUTLINE: This is a multicenter study.
Patients are stratified according to pathologic stage (intermediate high-risk vs very high-risk), histologic subtype (clear cell vs non-clear cell), and performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.
* Arm I: Patients receive oral everolimus once daily on days 1-42. Treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral placebo once daily on days 1-42. Treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.
Archived tumor tissue, plasma, and whole blood samples may be collected periodically for biomarker analysis and other translational studies.
After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 8 years.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Kidney Cancer
Eligibility Criteria
DISEASE CHARACTERISTICS:
* Histologically or cytologically confirmed renal cell carcinoma
* Clear cell or non-clear cell allowed
* No disease of the collecting duct or medullary carcinoma
* Considered pathologically either intermediate high-risk or very high-risk disease
* No history of distant metastases
* Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are eligible
* Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes
* Surgical margins must be negative
* Patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive)
* Patients must be registered within 84 days after the date of the first surgical resection of the first tumor
* No evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy and within 28 days before registration
* MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT scan of the chest may be substituted if the patient is not able to have CT scans with IV contrast
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Serum creatinine ≤ 2.0 times upper limit of normal (ULN) OR calculated creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 times ULN
* SGOT and SGPT ≤ 2.5 times ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception during and for up to 8 weeks after completion of study treatment
* Able to take oral medications
* Patients must not have any of the following:
* NYHA class III-IV cardiac disease (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort)
* Unstable angina pectoris
* Myocardial infarction within the past 6 months
* Serious uncontrolled cardiac arrhythmia
* Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C)
* HBV and HCV testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
* Must be able to take oral medications
* No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* No known history of HIV seropositivity
* No known uncontrolled, underlying pulmonary disease (spirometry and DLCO ≤ 50% of predicted OR oxygen saturation ≤ 88% at rest on room air)
* No uncontrolled hyperlipidemia (fasting serum cholesterol \> 300 mg/dL AND fasting triglycerides \> 2.5 times ULN) obtained within 28 days prior to registration
* Optimal lipid control must be achieved before registration and monitored during protocol treatment
* No uncontrolled diabetes mellitus (defined by fasting serum glucose \> 1.5 times ULN) obtained within 28 days prior to registration.
* Optimal glucose control must be achieved before registration and monitored during protocol treatment
* No prior malignancies except for any of the following:
* Adequately treated basal cell or squamous cell skin cancer
* In situ cervical cancer
* Adequately treated stage I or stage II cancer from which the patient is currently in complete remission
* Any other cancer from which the patient has been disease-free for 5 years
* No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients
* No contraindications to receiving either IV iodine-based contrast or gadolinium
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Patients must have recovered from any surgery-related complications
* No prior anticancer therapy for renal cell carcinoma including systemic therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical metastasectomy, or radiotherapy
* More than 14 days since prior and no concurrent strong CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, or ritonavir) or strong CYP3A4 inducers (i.e., phenytoin, rifampin, or rifabutin)
* More than 7 days since prior and no concurrent live vaccines
* No other concurrent anticancer agents including investigational agents
* No concurrent chronic treatment with systemic steroids or another immunosuppressive agent
* Topical or inhaled corticosteroids are allowed
* Histologically or cytologically confirmed renal cell carcinoma
* Clear cell or non-clear cell allowed
* No disease of the collecting duct or medullary carcinoma
* Considered pathologically either intermediate high-risk or very high-risk disease
* No history of distant metastases
* Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are eligible
* Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes
* Surgical margins must be negative
* Patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive)
* Patients must be registered within 84 days after the date of the first surgical resection of the first tumor
* No evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy and within 28 days before registration
* MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT scan of the chest may be substituted if the patient is not able to have CT scans with IV contrast
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Serum creatinine ≤ 2.0 times upper limit of normal (ULN) OR calculated creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 times ULN
* SGOT and SGPT ≤ 2.5 times ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception during and for up to 8 weeks after completion of study treatment
* Able to take oral medications
* Patients must not have any of the following:
* NYHA class III-IV cardiac disease (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort)
* Unstable angina pectoris
* Myocardial infarction within the past 6 months
* Serious uncontrolled cardiac arrhythmia
* Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C)
* HBV and HCV testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
* Must be able to take oral medications
* No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* No known history of HIV seropositivity
* No known uncontrolled, underlying pulmonary disease (spirometry and DLCO ≤ 50% of predicted OR oxygen saturation ≤ 88% at rest on room air)
* No uncontrolled hyperlipidemia (fasting serum cholesterol \> 300 mg/dL AND fasting triglycerides \> 2.5 times ULN) obtained within 28 days prior to registration
* Optimal lipid control must be achieved before registration and monitored during protocol treatment
* No uncontrolled diabetes mellitus (defined by fasting serum glucose \> 1.5 times ULN) obtained within 28 days prior to registration.
* Optimal glucose control must be achieved before registration and monitored during protocol treatment
* No prior malignancies except for any of the following:
* Adequately treated basal cell or squamous cell skin cancer
* In situ cervical cancer
* Adequately treated stage I or stage II cancer from which the patient is currently in complete remission
* Any other cancer from which the patient has been disease-free for 5 years
* No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients
* No contraindications to receiving either IV iodine-based contrast or gadolinium
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Patients must have recovered from any surgery-related complications
* No prior anticancer therapy for renal cell carcinoma including systemic therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical metastasectomy, or radiotherapy
* More than 14 days since prior and no concurrent strong CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, or ritonavir) or strong CYP3A4 inducers (i.e., phenytoin, rifampin, or rifabutin)
* More than 7 days since prior and no concurrent live vaccines
* No other concurrent anticancer agents including investigational agents
* No concurrent chronic treatment with systemic steroids or another immunosuppressive agent
* Topical or inhaled corticosteroids are allowed
Inclusion Criteria
DISEASE CHARACTERISTICS:
* Histologically or cytologically confirmed renal cell carcinoma
* Clear cell or non-clear cell allowed
* No disease of the collecting duct or medullary carcinoma
* Considered pathologically either intermediate high-risk or very high-risk disease
* No history of distant metastases
* Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are eligible
* Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes
* Surgical margins must be negative
* Patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive)
* Patients must be registered within 84 days after the date of the first surgical resection of the first tumor
* No evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy and within 28 days before registration
* MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT scan of the chest may be substituted if the patient is not able to have CT scans with IV contrast
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Serum creatinine ≤ 2.0 times upper limit of normal (ULN) OR calculated creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 times ULN
* SGOT and SGPT ≤ 2.5 times ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception during and for up to 8 weeks after completion of study treatment
* Able to take oral medications
* Patients must not have any of the following:
* NYHA class III-IV cardiac disease (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort)
* Unstable angina pectoris
* Myocardial infarction within the past 6 months
* Serious uncontrolled cardiac arrhythmia
* Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C)
* HBV and HCV testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
* Must be able to take oral medications
* No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* No known history of HIV seropositivity
* No known uncontrolled, underlying pulmonary disease (spirometry and DLCO ≤ 50% of predicted OR oxygen saturation ≤ 88% at rest on room air)
* No uncontrolled hyperlipidemia (fasting serum cholesterol \> 300 mg/dL AND fasting triglycerides \> 2.5 times ULN) obtained within 28 days prior to registration
* Optimal lipid control must be achieved before registration and monitored during protocol treatment
* No uncontrolled diabetes mellitus (defined by fasting serum glucose \> 1.5 times ULN) obtained within 28 days prior to registration.
* Optimal glucose control must be achieved before registration and monitored during protocol treatment
* No prior malignancies except for any of the following:
* Adequately treated basal cell or squamous cell skin cancer
* In situ cervical cancer
* Adequately treated stage I or stage II cancer from which the patient is currently in complete remission
* Any other cancer from which the patient has been disease-free for 5 years
* No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients
* No contraindications to receiving either IV iodine-based contrast or gadolinium
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Patients must have recovered from any surgery-related complications
* No prior anticancer therapy for renal cell carcinoma including systemic therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical metastasectomy, or radiotherapy
* More than 14 days since prior and no concurrent strong CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, or ritonavir) or strong CYP3A4 inducers (i.e., phenytoin, rifampin, or rifabutin)
* More than 7 days since prior and no concurrent live vaccines
* No other concurrent anticancer agents including investigational agents
* No concurrent chronic treatment with systemic steroids or another immunosuppressive agent
* Topical or inhaled corticosteroids are allowed
* Histologically or cytologically confirmed renal cell carcinoma
* Clear cell or non-clear cell allowed
* No disease of the collecting duct or medullary carcinoma
* Considered pathologically either intermediate high-risk or very high-risk disease
* No history of distant metastases
* Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are eligible
* Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes
* Surgical margins must be negative
* Patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive)
* Patients must be registered within 84 days after the date of the first surgical resection of the first tumor
* No evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy and within 28 days before registration
* MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT scan of the chest may be substituted if the patient is not able to have CT scans with IV contrast
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Serum creatinine ≤ 2.0 times upper limit of normal (ULN) OR calculated creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 times ULN
* SGOT and SGPT ≤ 2.5 times ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception during and for up to 8 weeks after completion of study treatment
* Able to take oral medications
* Patients must not have any of the following:
* NYHA class III-IV cardiac disease (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort)
* Unstable angina pectoris
* Myocardial infarction within the past 6 months
* Serious uncontrolled cardiac arrhythmia
* Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C)
* HBV and HCV testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
* Must be able to take oral medications
* No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* No known history of HIV seropositivity
* No known uncontrolled, underlying pulmonary disease (spirometry and DLCO ≤ 50% of predicted OR oxygen saturation ≤ 88% at rest on room air)
* No uncontrolled hyperlipidemia (fasting serum cholesterol \> 300 mg/dL AND fasting triglycerides \> 2.5 times ULN) obtained within 28 days prior to registration
* Optimal lipid control must be achieved before registration and monitored during protocol treatment
* No uncontrolled diabetes mellitus (defined by fasting serum glucose \> 1.5 times ULN) obtained within 28 days prior to registration.
* Optimal glucose control must be achieved before registration and monitored during protocol treatment
* No prior malignancies except for any of the following:
* Adequately treated basal cell or squamous cell skin cancer
* In situ cervical cancer
* Adequately treated stage I or stage II cancer from which the patient is currently in complete remission
* Any other cancer from which the patient has been disease-free for 5 years
* No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients
* No contraindications to receiving either IV iodine-based contrast or gadolinium
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Patients must have recovered from any surgery-related complications
* No prior anticancer therapy for renal cell carcinoma including systemic therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical metastasectomy, or radiotherapy
* More than 14 days since prior and no concurrent strong CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, or ritonavir) or strong CYP3A4 inducers (i.e., phenytoin, rifampin, or rifabutin)
* More than 7 days since prior and no concurrent live vaccines
* No other concurrent anticancer agents including investigational agents
* No concurrent chronic treatment with systemic steroids or another immunosuppressive agent
* Topical or inhaled corticosteroids are allowed
Gender
All
Gender Based
false
Keywords
stage I renal cell cancer
stage II renal cell cancer
stage III renal cell cancer
clear cell renal cell carcinoma
papillary renal cell carcinoma
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
120 Years
Minimum Age
18 Years
NCT Id
NCT01120249
Org Class
Network
Org Full Name
SWOG Cancer Research Network
Org Study Id
S0931
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study
Primary Outcomes
Outcome Description
To compare 5-year recurrence-free survival in renal carcinoma participants randomly assigned to 54 weeks of everolimus versus 54 weeks of placebo after nephrectomy or partial nephrectomy. Recurrence-free survival is defined as From date of registration to date of first documentation of recurrence or death due to any cause. Participants last known to be alive and recurrence-free are censored at date of last contact. Recurrence is defined as positive cytology or biopsy and/or progressively enlarging solid mass as evidenced by CT or MRI scans.
Outcome Measure
5-year Recurrence-free Survival (RFS)
Outcome Time Frame
5 years from registration
Secondary Ids
Secondary Id
S0931
Secondary Id
U10CA032102
Secondary Id
NCI-2011-02028
Secondary Outcomes
Outcome Description
To compare 5-year overall survival in those patients randomized to everolimus versus those randomized to placebo. Overall survival is defined as time from date of registration to date of death due to any cause or patients last known to be alive are censored at their last contact date.
Outcome Time Frame
5 years from registration
Outcome Measure
5-year Overall Survival (OS)
Outcome Description
Number of participants with Grade 3-5 adverse events that are possibly, probably or definitely related to study drug are reported. Measured using CTCAE v4.0.
Outcome Time Frame
Up to 54 weeks of treatment
Outcome Measure
Frequency and Severity of Toxicities
See Also Links
Url
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
120
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Karen Green
Investigator Email
kgreen@wphospital.org
Investigator Phone