Kidney Cancer
Conditions
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
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.
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.
Interventions
DRUGeverolimus
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Recurrence-free Survival (RFS) | 5 years from registration | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Overall Survival (OS) | 5 years from registration | 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. |
| Frequency and Severity of Toxicities | Up to 54 weeks of treatment | 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. |
Countries
Puerto Rico, United States
Participant flow
Pre-assignment details
1545 total participants were randomly assigned; 770 on the placebo arm and 775 on the everolimus arm. 46 participants were deemed ineligible. Reasons for ineligibility include insufficient imaging or unable to rule out residual or metastatic disease, evidence of residual or metastatic disease, not intermediate-high or very-high risk, other active or recent cancer, and ineligible histology. This leaves 1499 eligible participants (744 placebo, 755 everolimus).
Participants by arm
| Arm | Count |
|---|---|
| Placebo 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. | 744 |
| Everolimus 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. | 755 |
| Total | 1,499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 276 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease recurrence | 107 | 57 |
| Overall Study | No protocol treatment received | 21 | 15 |
| Overall Study | Other reasons, not protocol specified | 29 | 22 |
| Overall Study | Participant refusal | 34 | 42 |
Baseline characteristics
| Characteristic | Everolimus | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 58 years |
| Histology Clear Cell | 626 Participants | 1248 Participants | 622 Participants |
| Histology Non-clear cell, Chromophobe | 53 Participants | 99 Participants | 46 Participants |
| Histology Non-clear cell, Other | 19 Participants | 43 Participants | 24 Participants |
| Histology Non-clear cell, Papillary | 57 Participants | 109 Participants | 52 Participants |
| Nephrectomy Partial | 66 Participants | 148 Participants | 82 Participants |
| Nephrectomy Radical | 689 Participants | 1351 Participants | 662 Participants |
| Pathological Lymph Node Status pN0 | 219 Participants | 439 Participants | 220 Participants |
| Pathological Lymph Node Status pN+ (fully resected) | 58 Participants | 115 Participants | 57 Participants |
| Pathological Lymph Node Status pNx (clinically N0) | 478 Participants | 945 Participants | 467 Participants |
| Pathological T Stage pT1 | 62 Participants | 133 Participants | 71 Participants |
| Pathological T Stage pT2 | 147 Participants | 305 Participants | 158 Participants |
| Pathological T Stage pT3 | 525 Participants | 1023 Participants | 498 Participants |
| Pathological T Stage pT4 | 17 Participants | 31 Participants | 14 Participants |
| Pathological T Stage pTX | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 11 Participants | 31 Participants | 20 Participants |
| Race/Ethnicity, Customized Race Black | 34 Participants | 61 Participants | 27 Participants |
| Race/Ethnicity, Customized Race Other/unknown | 22 Participants | 49 Participants | 27 Participants |
| Race/Ethnicity, Customized Race White | 688 Participants | 1358 Participants | 670 Participants |
| Risk Group Intermediate-high | 343 Participants | 680 Participants | 337 Participants |
| Risk Group Very high | 412 Participants | 819 Participants | 407 Participants |
| Sex: Female, Male Female | 235 Participants | 457 Participants | 222 Participants |
| Sex: Female, Male Male | 520 Participants | 1042 Participants | 522 Participants |
| Zubrod Performance Status 0 | 603 Participants | 1191 Participants | 588 Participants |
| Zubrod Performance Status 1 | 152 Participants | 308 Participants | 156 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 151 / 744 | 139 / 755 |
| other Total, other adverse events | 649 / 723 | 716 / 740 |
| serious Total, serious adverse events | 68 / 723 | 154 / 740 |
Outcome results
Primary
5-year Recurrence-free Survival (RFS)
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.
Time frame: 5 years from registration
Population: 1545 total participants were randomly assigned; 770 on the placebo arm and 775 on the everolimus arm. 46 participants were deemed ineligible. Reasons for ineligibility include insufficient imaging or unable to rule out residual or metastatic disease, evidence of residual or metastatic disease, not intermediate-high or very-high risk, other active or recent cancer, and ineligible histology. This leaves 1499 eligible participants (744 placebo, 755 everolimus).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 5-year Recurrence-free Survival (RFS) | 63 percentage of paticipants |
| Everolimus | 5-year Recurrence-free Survival (RFS) | 67 percentage of paticipants |
Secondary
5-year Overall Survival (OS)
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.
Time frame: 5 years from registration
Population: 1545 total participants were randomly assigned; 770 on the placebo arm and 775 on the everolimus arm. 46 participants were deemed ineligible. Reasons for ineligibility include insufficient imaging or unable to rule out residual or metastatic disease, evidence of residual or metastatic disease, not intermediate-high or very-high risk, other active or recent cancer, and ineligible histology. This leaves 1499 eligible participants (744 placebo, 755 everolimus).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 5-year Overall Survival (OS) | 85 percentage of paticipants |
| Everolimus | 5-year Overall Survival (OS) | 87 percentage of paticipants |
Secondary
Frequency and Severity of Toxicities
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.
Time frame: Up to 54 weeks of treatment
Population: Participants who received at least one dose of protocol treatment and were not excluded from safety analysis per the study chairs request.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Frequency and Severity of Toxicities | Skin and subcutaneous tissue disorders - Other | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Hyponatremia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Skin infection | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Lymphocyte count decreased | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Soft tissue infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Nausea | 3 Participants |
| Placebo | Frequency and Severity of Toxicities | Syncope | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Mucositis oral | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Tooth infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypophosphatemia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Upper respiratory infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Multi-organ failure | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Urinary tract infection | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Hyperkalemia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Vomiting | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Myocardial infarction | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Weight gain | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypotension | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Wheezing | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Nail infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Wound infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Abdominal infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Nervous system disorders - Other, specify | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Abdominal pain | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Hoarseness | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Acidosis | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Neutrophil count decreased | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Acute kidney injury | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypoxia | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Agitation | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Non-cardiac chest pain | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Alanine aminotransferase increased | 3 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypertension | 20 Participants |
| Placebo | Frequency and Severity of Toxicities | Allergic reaction | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Obesity | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Anemia | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | INR increased | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Anorexia | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Pain | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Aortic valve disease | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Thromboembolic event | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Arthralgia | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Pain in extremity | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Aspartate aminotransferase increased | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Immune system disorders - Other, specify | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Back pain | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Peripheral sensory neuropathy | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Bone infection | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypertriglyceridemia | 13 Participants |
| Placebo | Frequency and Severity of Toxicities | Bullous dermatitis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Photosensitivity | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Cholesterol high | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Infections and infestations - Other, specify | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Chronic kidney disease | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Pneumonitis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Colitis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypercalcemia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Colonic perforation | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Proteinuria | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Creatinine increased | 2 Participants |
| Placebo | Frequency and Severity of Toxicities | Irritability | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Dehydration | 3 Participants |
| Placebo | Frequency and Severity of Toxicities | Pruritus | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Diarrhea | 5 Participants |
| Placebo | Frequency and Severity of Toxicities | Hyperuricemia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Dizziness | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Rash acneiform | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Dry skin | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Laryngeal mucositis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Dyspepsia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Rash maculo-papular | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Dyspnea | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Hemorrhoids | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Edema limbs | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Rash pustular | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Endocarditis infective | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Leukocytosis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Eye disorders - Other, specify | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Renal and urinary disorders - Other, specify | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Fatigue | 5 Participants |
| Placebo | Frequency and Severity of Toxicities | Hypokalemia | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Gastritis | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Resp, thoracic and mediastinal disorders - Other | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Gastrointestinal disorders - Other, specify | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Localized edema | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Generalized muscle weakness | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Seroma | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Glucose intolerance | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Hyperglycemia | 3 Participants |
| Placebo | Frequency and Severity of Toxicities | Headache | 1 Participants |
| Placebo | Frequency and Severity of Toxicities | Sinusitis | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Heart failure | 0 Participants |
| Placebo | Frequency and Severity of Toxicities | Lung infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Heart failure | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Syncope | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Nail infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Wound infection | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hemorrhoids | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hoarseness | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypercalcemia | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hyperglycemia | 37 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hyperkalemia | 4 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypertension | 31 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypertriglyceridemia | 85 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hyperuricemia | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypokalemia | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hyponatremia | 4 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypophosphatemia | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypotension | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Hypoxia | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | INR increased | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Immune system disorders - Other, specify | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Infections and infestations - Other, specify | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Irritability | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Laryngeal mucositis | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Leukocytosis | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Localized edema | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Lung infection | 5 Participants |
| Everolimus | Frequency and Severity of Toxicities | Lymphocyte count decreased | 5 Participants |
| Everolimus | Frequency and Severity of Toxicities | Mucositis oral | 103 Participants |
| Everolimus | Frequency and Severity of Toxicities | Multi-organ failure | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Myocardial infarction | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Nervous system disorders - Other, specify | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Neutrophil count decreased | 4 Participants |
| Everolimus | Frequency and Severity of Toxicities | Non-cardiac chest pain | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Obesity | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Pain | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Pain in extremity | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Peripheral sensory neuropathy | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Photosensitivity | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Pneumonitis | 9 Participants |
| Everolimus | Frequency and Severity of Toxicities | Proteinuria | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Pruritus | 7 Participants |
| Everolimus | Frequency and Severity of Toxicities | Rash acneiform | 16 Participants |
| Everolimus | Frequency and Severity of Toxicities | Rash maculo-papular | 15 Participants |
| Everolimus | Frequency and Severity of Toxicities | Rash pustular | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Renal and urinary disorders - Other, specify | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Resp, thoracic and mediastinal disorders - Other | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Seroma | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Sinusitis | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Skin and subcutaneous tissue disorders - Other | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Skin infection | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Soft tissue infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Thromboembolic event | 4 Participants |
| Everolimus | Frequency and Severity of Toxicities | Tooth infection | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Upper respiratory infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Urinary tract infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Vomiting | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Weight gain | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Wheezing | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Abdominal infection | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Abdominal pain | 7 Participants |
| Everolimus | Frequency and Severity of Toxicities | Acidosis | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Acute kidney injury | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Agitation | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Alanine aminotransferase increased | 6 Participants |
| Everolimus | Frequency and Severity of Toxicities | Allergic reaction | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Anemia | 12 Participants |
| Everolimus | Frequency and Severity of Toxicities | Anorexia | 4 Participants |
| Everolimus | Frequency and Severity of Toxicities | Aortic valve disease | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Arthralgia | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Aspartate aminotransferase increased | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Back pain | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Bone infection | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Bullous dermatitis | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Cholesterol high | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Chronic kidney disease | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Colitis | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Colonic perforation | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Creatinine increased | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Dehydration | 8 Participants |
| Everolimus | Frequency and Severity of Toxicities | Diarrhea | 11 Participants |
| Everolimus | Frequency and Severity of Toxicities | Dizziness | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Dry skin | 5 Participants |
| Everolimus | Frequency and Severity of Toxicities | Dyspepsia | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Dyspnea | 6 Participants |
| Everolimus | Frequency and Severity of Toxicities | Edema limbs | 3 Participants |
| Everolimus | Frequency and Severity of Toxicities | Endocarditis infective | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Eye disorders - Other, specify | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Fatigue | 27 Participants |
| Everolimus | Frequency and Severity of Toxicities | Gastritis | 0 Participants |
| Everolimus | Frequency and Severity of Toxicities | Gastrointestinal disorders - Other, specify | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Generalized muscle weakness | 1 Participants |
| Everolimus | Frequency and Severity of Toxicities | Glucose intolerance | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Headache | 2 Participants |
| Everolimus | Frequency and Severity of Toxicities | Nausea | 0 Participants |