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Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable) |
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Documented evidence of advanced RCC |
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At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria |
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Lymph node (LN) lesion that measures at least 1 dimension as =1.5 cm in the short axis |
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Non-nodal lesion that measures ≥1.0 cm in the longest diameter |
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The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion |
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Male or female subjects age ≥18 years (or any age >18 years of age (if that age is considered to be an adult per the local jurisdiction) at the time of informed consent |
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Karnofsky Performance Status (KPS) of ≥70 |
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Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week before the Cycle 1/Day 1 |
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Adequate renal function defined as calculated creatinine clearance =30 mL/min per the Cockcroft and Gault formula |
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Adequate bone marrow function defined by |
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Absolute neutrophil count (ANC) ≥1500/mm3 |
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Platelets ≥100,000/mm3 |
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Hemoglobin ≥9 g/dL |
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Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5 (except for subjects on warfarin therapy where INR must be =3.0 prior to randomization) |
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Adequate liver function defined by |
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Total bilirubin ≤1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome |
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Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN), unless there are bone metastases. Subjects with ALP values >3 times the ULN and known to have bone metastases can be included |
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Provide written informed consent |
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Willing and able to comply with all aspects of the protocol |
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Subjects who have received any systemic anticancer therapy for RCC, including anti-VEGF therapy, or any systemic investigational anticancer agent. Prior adjuvant treatment with an investigational anticancer agent is not allowed unless the investigator can provide evidence of subject’s randomization to placebo arm
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Subjects with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment
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Active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months. Subjects with history of localized & low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no PSA recurrence within the past 5 years
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Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start
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Subjects who are using other investigational agents or who had received investigational drugs ≤4 weeks prior to study treatment start
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Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed within 30 days of C1D1
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Subjects with proteinuria >1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible
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Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) and/or fasting triglycerides level >2.5 x ULN. NOTE: these subjects can be included after initiation or adjustment of lipid lowering medication
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Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN
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NOTE: these subjects can be included after initiation or adjustment of glucose-lowering medication
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Prolongation of QTc interval to >480 ms
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Subjects who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
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Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib, everolimus, and sunitinib
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Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
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Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
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Significant cardiovascular impairment within 6 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke, cardiac arrhythmia associated with significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by MUGA or echocardiogram
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Active infection (any infection requiring systemic treatment)
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Subjects known to be positive for Human Immunodeficiency Virus (HIV)
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Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected)
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Known history of, or any evidence of, interstitial lung disease
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Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
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Any medical or other condition that in the opinion of the investigator(s) would preclude the subject’s participation in a clinical study
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Subjects with a diagnosis of immunodeficiency or who are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5 mg/d of prednisone or equivalent) may be approved after consultation with the sponsor
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Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
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Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug
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Females of childbearing potential who
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do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation ie
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total abstinence (if it is their preferred and usual lifestyle)
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an intrauterine device (IUD) or hormone-releasing system (IUS)
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a contraceptive implant
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an oral contraceptive (with additional barrier method) OR
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do not have a vasectomized partner with confirmed azoospermia
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NOTES
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All females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]
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Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study
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Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to use condom + spermicide OR have a female partner who does not meet the criteria above (ie, is of childbearing potential and not practicing highly effective contraception throughout the study period), starting with the first dose of study therapy through 120 days after the last dose of study therapy, unless sexually abstinent. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
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Known intolerance to any of the study drugs (or any of the excipients)
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