Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects With Advanced Renal Cell Carcinoma (CLEAR)
Brief Summary: The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review \[IIR\] using Response Evaluation Criteria in Solid Tumors \[RECIST 1.1\]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).


Options:
A: Inclusion Criteria:

* Renal cell carcinoma with a predominant clear cell component confirmed by histology.
* Advanced disease: metastatic AND, not suitable for resection
* Male or female, aged 18 years or older
* ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 or 1
* Low or intermediate MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk score,i.e. no more than 2 of the following:

  * Karnofsky performance status (\<80%)
  * Low serum hemoglobin (≤ 13 g/dL for males and ≤ 11.5 g/dL for females)
  * High corrected serum calcium (≥ 10 mg/dL)
* Target and/or non-target lesions according to RECIST 1.1 ( Response Evaluation Criteria in Solid Tumors)
* Expected survival of at least 3 months.
* No prior systemic treatment. But adjuvant treatment is ok if stopped from ≥ 24 months
* Adequate bone marrow function as shown by:
* Adequate liver function as shown by:
* Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN (upper limit of normal)
* Left ventricular ejection fraction ≥55% on gated cardiac blood pool scan, or normal left ventricular function and fractional shortening on echocardiogram (according to institutional limits).
* SBP (systolic blood pressure) ≤140mmHg and DBP (diastolic blood pressure)

  * 90mmHg (it is acceptable to initiate antihypertensive treatment prior to registration to achieve these goals).
* Able to commence treatment within 7 days of registration.
* Willing and able to comply with follow-up and all other protocol requirements.
* Written informed consent

Exclusion Criteria:

* Prior treatment with VEGF-targeting agents or multi-kinase inhibitors or mTOR-targeting agents
* Active central nervous system metastases.
* Other malignancy diagnosed within the last 5 years, except the following if adequately treated: superficial squamous cell carcinoma or basal cell carcinoma of skin, superficial bladder cancer (T1 and G1 or T1 and G2), stage 1 cervical cancer.
* Treatment with an investigational agent in the last 4 w.
* Known to be HIV positive.
* Evidence of chronic hepatitis due to hepatitis B virus (HBV) or hepatitis C virus (HCV)
* Clinically significant heart disease (NYHA Class III or IV)
* History of hypertension requiring hospitalization.
* Other serious illnesses,
* Immunotherapy or chemotherapy in the last 4 w (6 weeks for nitrosoureas)
* Major surgery in the last 4 w, or planned in the next 6 w
* Radiation therapy in the last 2 w, or planned in the next 6 w
* NCI CTCAE (Common Toxicity Criteria for Adverse Effects) version 4.0 grade 3 or worse hemorrhage in last 4 w.
* Any of the following in the last year: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
* Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
* Ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 grade ≥2, atrial fibrillation of any grade, or prolongation of the corrected QT interval (QTc) to \>450 msec for males or \>470 msec for females
* Uncontrolled diabetes as defined by fasting serum glucose \>1.5 X ULN.
* Pregnancy,lactation. Inadequate contraception.
* Known allergy or hypersensitivity to everolimus, sunitinib or iodine.
* Medical or psychiatric condition that compromises the patient's ability to give informed consent.
B: Key Inclusion Criteria:

* Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
* Metastatic (American Joint Committee on Cancer \[AJCC\] Stage IV) RCC
* No prior systemic therapy for mRCC
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
* Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration \[FNA\] and bone metastases samples are not acceptable for submission).
* Molecular group has to be determined prior to randomization.
* Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis.

Key Exclusion Criteria:

* Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant oedema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
* Prior systemic treatment with vascular endothelial growth factor (VEGF) or VEGF receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free interval of more than 1 year.
* Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
* Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
* Any condition requiring systemic treatment with corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \>10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Uncontrolled adrenal insufficiency.
* Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as \>450 msec for males and \>470 msec for females, where QTcF = QT / 3√RR.
* Poorly controlled hypertension (defined as systolic blood pressure (SBP) of \>150 mmHg or diastolic blood pressure (DBP) of \>90 mmHg), despite antihypertensive therapy.
* History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
* History of cerebrovascular accident including transient ischemic attack within the past 12 months.
* History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin.
* History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
* Known history of COPD (of any stage).
* Known history of uveitis or complaint of double vision.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
* Serious, non-healing wound or ulcer.
* Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
* Any requirement for anti-coagulation, except for low molecular weight heparin.
* Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
* Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the Investigator's opinion, would increase the risk associated with study participation or study drug administration, or interfere with the interpretation of safety results.
* Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.
* Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug.
* Focal radiation therapy less than 14 days prior to the first dose of study drug.
* Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
* Any of the following laboratory test findings:

  1. WBC \<2,000/mm3
  2. Hemoglobin ≤9.0 g/dL
  3. Neutrophils \<1,500/mm3
  4. Platelets \<100,000/mm3
  5. AST or ALT \>3 x ULN (\>5 x ULN if liver metastases are present)
  6. Lipase and amylase \> 1.5 ULN
  7. Total Bilirubin \>1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \<3.0 mg/dL)
  8. Serum creatinine \>1.5 x ULN or creatinine clearance \<40 mL/min (measured or calculated by Cockroft-Gault formula)
  9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if \> 1.0 g of protein patient will not be included.
C: Inclusion Criteria:

1. Pathologic confirmation of metastatic or locally advanced RCC with a major clear cell component.
2. Measurable disease by RECIST criteria.
3. Age \>/= 18 years
4. ECOG performance status 0-2 or Karnofsky Performance Status \>/= 60%
5. Meets criteria for poor-risk defined as 3 or more of the following: ECOG performance status 2, anemia (hemoglobin lower than reference range), elevated serum LDH \> 1.5x upper limit of normal (ULN), hypercalcemia (corrected serum calcium level \> upper limit of normal), time from initial RCC diagnosis to registration on this trial \< 1 year, and \> 1 metastatic organ sites.
6. Adequate organ and marrow function within 14 days of registration as defined below: a) Absolute neutrophil count \>/=1,500/µL b) Platelets \>/=100,000/µL c) Hgb \>/= 9.0 g/dL (transfusion allowed) d) Renal: serum creatinine \</= 1.5 x ULN or calculated CrCl \>/= 40 cc/min and random urine protein:creatinine ratio (UPC) \< 1 or 24-hr urine protein \< 1g e) Liver: total bilirubin \</= 1.5 mg/dl; AST (SGOT) and ALT (SGPT) \</= 2.5 x ULN for subjects without evidence of liver metastases, \</= 5 x ULN for subjects with documented liver metastases f) INR \</= 1.2 x ULN; PTT \</= 1.5 x ULN. Therapeutic anticoagulation with warfarin is allowed if target INR \</= 3 on a stable dose of warfarin or on a stable dose of LMW heparin for \> 2 weeks (14 days) at time of randomization.
7. Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test within 14 days of study registration. Pregnancy test must be repeated if performed \> 14 days before starting study drug.

Exclusion Criteria:

1. Prior malignancy, except for non-melanoma skin cancer, in situ carcinoma of any site, or other cancers for which the patient has been adequately treated and disease free for 2 years
2. Prior targeted therapy (anti-VEGF agents or mTOR inhibitors) including adjuvant therapy, and prior chemotherapy for mRCC. However, prior immunotherapy (cytokines or vaccines) is allowed.
3. Any experimental drug while on this study; however, concomitant bone targeted therapy (bisphosphonates or the anti-RANK ligand denosumab) is allowed.
4. Uncontrolled brain metastases and infections. Patients with brain metastases treated with Gamma Knife (GK) or whole brain radiation within 24 hours of registration.
5. History of stroke within 6 months of registration
6. Clinically significant cardiovascular disease, defined as myocardial infarction (or unstable angina) within 6 months of registration, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management. However, treated and controlled or stable/not clinically significant cardiovascular disease is allowed per evaluation by cardiologist.
7. Uncontrolled hypertension (home blood pressure readings are permitted) or prior history of hypertensive crisis or hypertensive encephalopathy; however, treatment of hypertension with medications is permitted.
8. History of uncontrolled hemoptysis (\>/= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
9. Significant vascular disease including aortic aneurysm, aortic dissection.
10. Symptomatic peripheral vascular disease
11. Pregnancy
12. HIV-positive patients receiving combination anti-retroviral therapy
13. Coagulopathy or bleeding diathesis
14. Concomitant treatment with rifampin, St. John's wort, or the cytochrome p450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital)
15. Major surgery within 28 days prior to registration
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device within 7 days prior to starting drug
17. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study registration
18. Serious non-healing wound
19. Baseline QTcB \>/= 470 msec.
D: Inclusion Criteria:

1. Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria:

   * Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (\>=) 1.5 cm in the short axis
   * Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (\>=) 1.5 centimeter (cm) in the short axis
   * Non-nodal lesion that measures greater than or equal to (\>=) 1.0 cm in the longest diameter
   * 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.

3.Karnofsky Performance Status (KPS) of \>=70 4.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal (\<=) 150/90 millimeter of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1 (C1/D1) 5.Adequate renal function defined as creatinine \<=1.5\*upper limit of normal (ULN); or for participants with creatinine greater than (\>) 1.5\*ULN, the calculated creatinine clearance \>=30 milliliters per minute (mL/min) (per the Cockcroft-Gault formula) is acceptable.

6.Adequate bone marrow function defined by:

* Absolute neutrophil count (ANC) \>=1500/cubic millimeter (mm\^3)
* Platelets \>=100,000/mm\^3
* Hemoglobin \>=9 grams per deciliter (g/dL) NOTE: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the previous 2 weeks.

  7.Adequate blood coagulation function defined by International Normalized ratio (INR) \<=1.5 unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range of intended use of anticoagulants.

  8.Adequate liver function defined by:
* Total bilirubin \<=1.5\*ULN except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
* 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. Participants with ALP values \>3\*ULN and known to have bone metastases can be included.

  9.Provide written informed consent. 10.Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

1. Participants who have received any systemic anticancer therapy for RCC, including anti-vascular endothelial growth factor (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 participant's randomization to placebo arm.
2. Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (example, 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 (example, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment
3. 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. Participants with history of localized \& low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no prostate specific antigen (PSA) recurrence within the past 5 years
4. 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
5. Participants who are using other investigational agents or who had received investigational drugs \<=4 weeks prior to study treatment start.
6. Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). Examples of live vaccines include, but are not limited to, measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (example, FluMist®) are live attenuated vaccines and are not allowed.
7. Participants with proteinuria \>1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein \>=1 g/24 h will be ineligible
8. Fasting total cholesterol \>300 milligram per deciliter (mg/dL) (or ˃7.75 millimole per liter (mmol/L)) and/or fasting triglycerides level ˃2.5 x upper limit of normal (ULN). Note: these participants can be included after initiation or adjustment of lipid-lowering medication
9. Uncontrolled diabetes as defined by fasting glucose \>1.5 times the ULN. Note: these participants can be included after initiation or adjustment of glucose-lowering medication
10. Prolongation of corrected QT (QTc) interval to \>480 milliseconds (ms)
11. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib, everolimus, and/or sunitinib.
13. Bleeding or thrombotic disorders or participants 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
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
15. Significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction, cerebrovascular accident, or cardiac arrhythmia associated with hemodynamic instability. The following is also excluded: left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multiple-gated acquisition MUGA scan or echocardiogram
16. Active infection (any infection requiring systemic treatment)
17. Participants known to be positive for Human Immunodeficiency Virus (HIV).
18. Known active Hepatitis B (example, Hepatitis B surface antigen (HBsAg) reactive) or Hepatitis C (example, hepatitis C virus ribonucleic acid (HCV RNA) \[qualitative\] is detected)
19. Known history of, or any evidence of, interstitial lung disease
20. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
21. Participants with a diagnosis of immunodeficiency or who are receiving chronic systemic steroid therapy (doses exceeding 10 mg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or equivalent) may be used during the study
22. Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (that is, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
23. 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.
24. Females of childbearing potential who:

    * Do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation, that is:
    * total abstinence (if it is their preferred and usual lifestyle)
    * an intrauterine device (IUD) or hormone-releasing system (IUS)
    * a contraceptive implant
    * an oral contraceptive (with additional barrier method) OR
    * Do not have a vasectomized partner with confirmed azoospermia. For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
25. 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 (that is, 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 participant.
26. Known intolerance to any of the study drugs (or any of the excipients)
27. Participant has had an allogenic tissue/solid organ transplant.

Answer: D