Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Carcinoma, Stage IV Renal Cell Cancer AJCC v7
Conditions
Brief summary
This randomized phase II trial studies different combinations of bevacizumab, temsirolimus, and sorafenib tosylate to see how well they work compared with bevacizumab alone in treating patients with kidney cancer that has spread to other places in the body. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab and sorafenib tosylate may stop the growth of tumor cells by blocking blood flow to the tumor. Temsirolimus and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving different combinations of bevacizumab, sorafenib tosylate, and temsirolimus may be more effective than bevacizumab alone in treating metastatic kidney cancer.
Detailed description
PRIMARY OBJECTIVES: I. To assess progression-free survival on each arm of combination targeted therapy (CTT) compared to that of bevacizumab alone. SECONDARY OBJECTIVES: I. To assess the significance of changes in tumor size over early time points as a predictor of progression-free survival (PFS). II. To quantify the number and percent of patients who have stable disease at 6 months of therapy (failure to progress) in each treatment arm of CTT in patients with metastatic renal cell carcinoma (RCC). III. To evaluate the safety of each treatment arm of combination targeted therapy (CTT) in patients with metastatic RCC. IV. To assess overall survival in each arm of the study. V. To assess the objective response rate in each treatment arm of CTT in patients with metastatic RCC. VI. To assess pathology, angiogenesis histology and to assess activation status of mitogen activated protein (MAP) kinase and vascular endothelial growth factor receptor 2 (VEGFR2) pathways and relate to clinical outcome. TERTIARY OBJECTIVES: I. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib (sorafenib tosylate) including angiogenesis, monooxygenases polymorphisms and multi-drug resistance (MDR). II. To relate changes in tumor perfusion and vascular permeability on serial dynamic contrast-enhanced magnetic resonance imaging (MRI) to clinical outcome and radiologic regression detected by other standard methods. III. To assess the potential of dynamic contrast-enhanced (DCE)-MRI imaging as a biomarker for response to therapy and/or as a prognostic indicator of disease progression. IV. To assess site readiness and ability in acquiring DCE-MRI data. V. To determine the relationship between tumor and blood biomarkers and clinical outcomes of patients treated with the combination of targeted agents. OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM A: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15. ARM B: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in Arm A. ARM C: Patients receive bevacizumab as in Arm A and sorafenib tosylate orally (PO) twice daily (BID) on days 1-5, 8-12, 15-19, and 22-26. ARM D: Patients receive sorafenib tosylate PO BID on days 1-28 and temsirolimus as in Arm B. In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for 5 years.
Interventions
BIOLOGICALBevacizumab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
DRUGSorafenib Tosylate
Given PO
DRUGTemsirolimus
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients will be required to have the clear cell variant of renal cell carcinoma with less than 25% of any other histology (including, but not limited to, papillary or chromophobe or oncocytic); there must be histologic confirmation by treating center of either primary or metastatic lesion * Patients will be required to have measurable metastatic disease that is not curable by standard radiation therapy or surgery; all sites must be assessed within 4 weeks prior to study entry * Previous nephrectomy is required with the following exceptions: * Primary tumor =\< 5 cm, or * Extensive liver (\> 30% of liver parenchymal) or multiple (\> 5) bone metastases, making nephrectomy a clinically questionable procedure * Unresectable primary tumor due to invasion into adjacent organs or encasing the aorta or vena cava * No prior cytotoxic chemotherapy; a maximum of one prior regimen of either vaccine or cytokine-based immunotherapy disease is permitted * No prior anti-angiogenic therapy including, but not limited to, SU11248, ZD6474 or VEGF Trap; no prior therapy with bevacizumab, mammalian target of rapamycin (mTOR) inhibitors (including, but not limited to, temsirolimus), or sorafenib will be allowed; thalidomide or interferon alpha (IFNalpha) are allowed either for adjuvant therapy or stage IV disease * No immunotherapy within 4 weeks of randomization; toxicities from immunotherapy must have resolved and a minimum of two weeks must pass prior to enrollment * Prior radiation therapy is permitted, but toxicities from radiation must have resolved and a minimum of 2 weeks must pass prior to randomization * No history or clinical evidence of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastasis, or history of stroke within the past 48 weeks * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy of greater than 12 weeks * Hemoglobin (Hgb) \>= 9.0 g/dL (transfusions allowed prior to enrollment) * White blood count (WBC) \>= 3,000/mm\^3 * Absolute granulocyte count (AGC) \>= 1,200/mm\^3 * Platelet count \>= 100,000/mm\^3 * Serum creatinine =\< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) \>= 55 ml/min * Total bilirubin =\< 1.5 x ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN (or =\< 5.0 x ULN in the presence of liver metastases) * International normalized ratio (INR) =\< 1.5 * Activated partial thromboplastin time (aPTT) within normal limits * Fasting cholesterol \< 350 mg/dL (9.0 mmol/L) * Fasting triglycerides \< 400 mg/dL (4.56 mmol/L) * Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for \>= 5 years prior to the time of randomization * No history of allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to sorafenib, temsirolimus or bevacizumab * No history of bleeding diathesis or coagulopathy * Any condition that impairs patient's ability to swallow pills will make patient ineligible * No major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization * No anticipated need for major surgery during the course of the study * No current or recent (within 4 weeks of enrollment) use of full-dose of anticoagulants or thrombolytic agents (except as required to maintain patency of preexisting or permanent indwelling IV catheters, for those patients receiving warfarin, INR must be =\< 1.5) * No clinically significant cardiovascular disease, defined as one of the following: * Patients with uncontrolled hypertension (blood pressure \> 150/100 mm/Hg at the time of enrollment); patients with hypertension and blood pressure =\< 150/100 mm/Hg on stable antihypertensive regimen are eligible * Myocardial infarction or unstable angina \< 24 weeks prior to registration * New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris * Grade II or greater peripheral vascular disease * No serious, non-healing wound, ulcer, or bone fracture * No significant proteinuria at baseline; urine protein must be screened within 2 weeks prior to randomization by urine analysis for urine protein creatinine (UPC) ratio; if UPC ratio is \> 0.5, 24-hour urine protein is to be obtained and the level must be \< 1000 mg for patient enrollment * NOTE: UPC ratio of spot urine is an estimation of the 24 urine protein excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm * No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics on day 0 or psychiatric illness/social situations that would limit compliance with study requirements * Patients currently taking any of the following cytochrome P450 enzyme-inducing drugs are ineligible: * Phenytoin * Carbamazepine * Phenobarbital * Rifampin * Pregnant and breastfeeding women are excluded from the study; breastfeeding should be discontinued while receiving therapy; patients must have pregnancy test within 7 days prior to patient randomization if woman is of child-bearing capacity * Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years | Progression-free survival is defined as time from randomization to clinical evidence of disease progression or death from any cause without progression. Patients alive without progression were censored at the date of last disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Stable Disease at 6 Months | Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years | Patients whose date of progression was after 6 months or who were disease-free at last follow-up beyond 6 months were considered to be stable at 6 months and all other patients were not. |
| Overall Survival | Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years | Overall survival was defined as the time from randomization to death. Patients alive at last contact were censored on the date of last contact. |
| Objective Response Rate | Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years | Response was assessed using Solid Tumor Response Criteria (RECIST). Patients with complete responses or partial responses are considered having an objective response. |
Countries
Peru, United States
Participant flow
Recruitment details
Participants were recruited from ECOG member institutions between September 14, 2007 and December 10, 2010 with a final accrual of 361 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Bevacizumab) Patients receive bevacizumab 10 mg/kg IV over 30-90 minutes on days 1 and 15 in a 28-day cycle. | 84 |
| Arm B (Bevacizumab and Temsirolimus) Patients receive temsirolimus 25 mg IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in Arm A in a 28-day cycle. | 80 |
| Arm C (Bevacizumab and Sorafenib) Patients receive bevacizumab 5 mg/kg IV over 30-90 minutes on days 1 and 15 and sorafenib 200 mg PO BID on days 1-5, 8-12, 15-19, and 22-26 in a 28-day cycle. | 83 |
| Arm D (Sorafenib and Temsirolimus) Patients receive sorafenib 200 mg PO BID on days 1-28 and temsirolimus as in Arm B in a 28-day cycle. | 84 |
| Total | 331 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 17 | 20 | 18 |
| Overall Study | Adverse events and progressive disease | 0 | 0 | 0 | 1 |
| Overall Study | Alternative therapy | 4 | 2 | 0 | 0 |
| Overall Study | Death | 2 | 2 | 4 | 3 |
| Overall Study | Disease progression | 59 | 43 | 48 | 49 |
| Overall Study | Ineligible | 4 | 7 | 7 | 7 |
| Overall Study | Joint decision of physician and patient | 1 | 0 | 0 | 0 |
| Overall Study | Never started treatment | 1 | 4 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 2 | 3 |
| Overall Study | Other complicated disease | 0 | 2 | 2 | 0 |
| Overall Study | Physician Decision | 1 | 4 | 1 | 0 |
| Overall Study | Relocation | 0 | 0 | 1 | 0 |
| Overall Study | Surgery | 1 | 0 | 0 | 1 |
| Overall Study | Symptomatic deterioration | 0 | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 8 | 5 | 7 |
Baseline characteristics
| Characteristic | Arm A (Bevacizumab) | Arm B (Bevacizumab and Temsirolimus) | Arm C (Bevacizumab and Sorafenib) | Arm D (Sorafenib and Temsirolimus) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 29 Participants | 31 Participants | 23 Participants | 118 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 51 Participants | 52 Participants | 61 Participants | 213 Participants |
| Region of Enrollment United States | 84 participants | 80 participants | 83 participants | 84 participants | 331 participants |
| Sex: Female, Male Female | 22 Participants | 25 Participants | 26 Participants | 17 Participants | 90 Participants |
| Sex: Female, Male Male | 62 Participants | 55 Participants | 57 Participants | 67 Participants | 241 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 80 / 88 | 86 / 86 | 89 / 90 | 90 / 91 |
| serious Total, serious adverse events | 39 / 88 | 66 / 86 | 74 / 90 | 76 / 91 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival is defined as time from randomization to clinical evidence of disease progression or death from any cause without progression. Patients alive without progression were censored at the date of last disease assessment.
Time frame: Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years
Population: Eligible, treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab) | Progression-free Survival (PFS) | 7.5 Months |
| Arm B (Bevacizumab and Temsirolimus) | Progression-free Survival (PFS) | 7.6 Months |
| Arm C (Bevacizumab and Sorafenib) | Progression-free Survival (PFS) | 9.2 Months |
| Arm D (Sorafenib and Temsirolimus) | Progression-free Survival (PFS) | 7.4 Months |
Comparison: Progression-free survival was compared between Arm B (bevacizumab and temsirolimus) and Arm A (bevacizumab alone) using stratified log rank test, stratified on prior cytokine or vaccine therapy and risk category (low/intermediate/high risk)p-value: 0.89Log Rank
Comparison: Progression-free survival was compared between Arm C (bevacizumab and sorafenib) and Arm A (bevacizumab alone) using stratified log rank test, stratified on prior cytokine or vaccine therapy and risk category (low/intermediate/high risk).p-value: 0.54Log Rank
Comparison: Progression-free survival was compared between Arm D (sorafenib and temsirolimus) and Arm A (bevacizumab alone) using stratified log rank test, stratified on prior cytokine or vaccine therapy and risk category (low/intermediate/high risk).p-value: 0.68Log Rank
Secondary
Objective Response Rate
Response was assessed using Solid Tumor Response Criteria (RECIST). Patients with complete responses or partial responses are considered having an objective response.
Time frame: Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years
Population: Eligible, treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab) | Objective Response Rate | 0.133 Proportion of patients |
| Arm B (Bevacizumab and Temsirolimus) | Objective Response Rate | 0.316 Proportion of patients |
| Arm C (Bevacizumab and Sorafenib) | Objective Response Rate | 0.305 Proportion of patients |
| Arm D (Sorafenib and Temsirolimus) | Objective Response Rate | 0.202 Proportion of patients |
Comparison: The response rate of each combination arm was compared to that of the bevacizumab alone arm.p-value: 0.0076Fisher Exact
Comparison: The response rate of each combination arm was compared to that of the bevacizumab alone arm.p-value: 0.0085Fisher Exact
Comparison: The response rate of each combination arm was compared to that of the bevacizumab alone arm.p-value: 0.3006Fisher Exact
Secondary
Overall Survival
Overall survival was defined as the time from randomization to death. Patients alive at last contact were censored on the date of last contact.
Time frame: Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years
Population: Eligible, treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab) | Overall Survival | 28.6 Months |
| Arm B (Bevacizumab and Temsirolimus) | Overall Survival | 24.7 Months |
| Arm C (Bevacizumab and Sorafenib) | Overall Survival | 27.5 Months |
| Arm D (Sorafenib and Temsirolimus) | Overall Survival | 24.3 Months |
Secondary
Proportion of Patients With Stable Disease at 6 Months
Patients whose date of progression was after 6 months or who were disease-free at last follow-up beyond 6 months were considered to be stable at 6 months and all other patients were not.
Time frame: Assessed every 2 cycles for the first 12 cycles, then every 3 cycles until treatment discontinuation, then every 8 weeks until disease progression or up to 5 years
Population: Eligible, treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab) | Proportion of Patients With Stable Disease at 6 Months | 0.548 Proportion of patients |
| Arm B (Bevacizumab and Temsirolimus) | Proportion of Patients With Stable Disease at 6 Months | 0.562 Proportion of patients |
| Arm C (Bevacizumab and Sorafenib) | Proportion of Patients With Stable Disease at 6 Months | 0.590 Proportion of patients |
| Arm D (Sorafenib and Temsirolimus) | Proportion of Patients With Stable Disease at 6 Months | 0.524 Proportion of patients |