Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma

Renal Cell Carcinoma Clinical Trial

— CLEAR  

Official 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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02811861
• Other study ID #: E7080-G000-307
• Secondary ID: KEYNOTE-5812016-
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 13, 2016
• Est. completion date: July 31, 2024

Study information

• Verified date: July 2023
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1069
• Est. completion date: July 31, 2024
• Est. primary completion date: August 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Renal Cell Carcinoma

Intervention

Drug:
• Lenvatinib

• Everolimus

• Pembrolizumab

• Sunitinib

Locations

Country	Name	City	State
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart
Australia	Macquarie University Hospital	Macquarie park
Australia	ICON Cancer Foundation	South Brisbane
Australia	Sunshine Hospital	St Albans
Austria	Medizinische Universitat Innsbruck	Innsbruck
Austria	Krankenhaus der barmherzigen Schwestern Linz	Linz
Austria	AKH - Medizinische Universität Wien	Vienna
Belgium	O.L.V Ziekenhuis	Aalst
Belgium	ZNA Middelheim	Antwerpen
Belgium	Imeldaziekenhuis	Bonheiden
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Jessa Ziekenhuis - Campus Virga Jesse	Hasselt
Belgium	Domaine Universitaire	Liege
Belgium	GZA Ziekenhuizen - Campus Sint-Augustinus	Wilrijk
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Centre de santé et de services sociaux Champlain-Charles-Le Moyne	Greenfield Park	Quebec
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	London Institute of Health Sciences	London	Ontario
Canada	Ottawa Hospital Cancer Centre	Ottawa	Ontario
Canada	Sunnybrook Research Institute - University of Toronto	Toronto	Ontario
Canada	BC Cancer Agency Vancouver Centre	Vancouver	British Columbia
Czechia	Fakultni nemocnice u sv. Anny v Brne	Brno
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni nemocnice Olomouc, Neurologicka klinika	Olomouc
Czechia	Thomayerova nemocnice	Praha 4
Czechia	Fakultni nemocnice v Motole	Praha 5
Czechia	Nemocnice Na Bulovce	Praha 8
France	ICO - Site Paul Papin	Angers	Maine Et Loire
France	Centre Georges François Leclerc	Dijon cedex
France	Clinique Victor Hugo - Centre Jean Bernard	Le Mans Cedex
France	Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes	Lyon
France	Institut Regional du Cancer de Montpellier	Montpellier
France	Hopital Europeen Georges Pompidou	Paris
France	Hopital la Petie Salpetriere	Paris
France	Boulevard du Professeur Jacques Monod	Saint Herblain
France	CHU Strasbourg - Nouvel Hopital Civil	Strasbourg
Germany	EISAI Trial site 5	Berlin
Germany	EISAI Trial site 6	Frankfurt	Hessen
Germany	EISAI Trial site 14	Greifswald	Mecklenburg-Vorpommern
Germany	EISAI Trial site 8	Hannover	Niedersachsen
Germany	EISAI Trial site 2	Homburg/Saar	Saarland
Germany	EISAI Trial site 7	München	Bayern
Germany	EISAI Trial site 13	Münster	Nordrhein Westfalen
Germany	EISAI Trial site 4	Stuttgart	Baden Wuerttemberg
Germany	EISAI Trial site 1	Tuebingen	Baden Wuerttemberg
Greece	General Hospital of Athens "Alexandra"	Athens
Greece	University of Patras Medical School	Patras
Greece	General Hospital Papageorgiou	Thessaloníki
Greece	Interbalkan Hospital of Thessaloniki	Thessaloníki
Ireland	Cork University Hospital,Wilton	Cork
Ireland	Adelaide and Meath Hospital Incorp The National Children's Hospital	Dublin
Ireland	Beaumont Hospital	Dublin
Ireland	University Hospital Galway	Galway
Israel	Assaf Harofeh Medical Center	Be'er Ya'aqov
Israel	Rambam MC	Haifa
Israel	Sapir Medical Center, Meir Hospital	Kfar-Saba
Israel	Rabin Medical Center-Beilinson Campus	Petah Tikva
Israel	Chaim Sheba Medical Center	Ramat-Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Ospedale San Donato	Arezzo
Italy	Azienda Ospedaliera Universitaria Policlinico SantOrsola Malpighi	Bologna
Italy	Azienda Unità Sanitaria Locale- Ravenna	Faenza	Ravenna
Italy	Istituto Nazionale per la Ricerca sul Cancro di Genova	Genova
Italy	Presidio Ospedaliero Vito Fazzi	Lecce
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST	Meldola
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	A.O.U. Policlinico di Modena	Modena
Italy	Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli	Napoli
Italy	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	I.R.C.S.S Fondazione Maugeri	Pavia
Italy	Azienda Ospedaliera Santa Maria Degli Angeli	Pordenone
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Italy	Universita Campus Bio-Medico di Roma	Rome
Japan	Facility #1	Aichi
Japan	Facility #1	Akita
Japan	Facility #1	Aomori
Japan	Facility #2	Chiba
Japan	Facility #1	Fukuoka
Japan	Facility #1	Hiroshima
Japan	Facility #1	Hokkaido
Japan	Facility #2	Hokkaido
Japan	Facility #1	Hyogo
Japan	Facility #1	Kagawa
Japan	Facility #2	Kanagawa
Japan	Facility #3	Kanagawa
Japan	Facility #1	Nagasaki
Japan	Facility #1	Nara
Japan	Facility #1	Niigata
Japan	Facility #1	Okayama
Japan	Facility #1	Osaka
Japan	Facility #2	Osaka
Japan	Facility #1	Saitama
Japan	Facility #1	Tokushima
Japan	Facility #1	Tokyo
Japan	Facility #2	Tokyo
Japan	Facility #3	Tokyo
Japan	Facility #4	Tokyo
Japan	Facility #5	Tokyo
Japan	Facility #6	Tokyo
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center: Medical Oncology Department	Seoul
Korea, Republic of	Asan Medical Center: Urology Department	Seoul
Korea, Republic of	Department of Internal Medicine Division of Hematology/Oncology Cancer center 11F	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Netherlands	Antoni van Leeuwenhoek	Amsterdam
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	UMC Utrecht	Utrecht
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie	Lublin
Poland	SPWSZ w Szczecinie im. Marii Sklodowskiej-Curie	Szczecin
Russian Federation	FSBI "Moscow scientific research oncology institute n.a. P.A. Gertsen" of MoH of RF	Moscow
Russian Federation	FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin - Department of Oncology	Moscow
Russian Federation	FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin - Department of Urology	Moscow
Russian Federation	FBHI Privolzhskiy District Medical Centre FMBA of Russia	Nizhniy Novgorod
Russian Federation	SBHI of Novosibirsk region "Novosibirsk Regional Oncological Dispensary"	Novosibirsk
Russian Federation	FSBI "National Medical Research Radiological Center" of the MoH of the RF	Obninsk
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO l'Hospitalet - Hospital Duran I Reynals	Barcelona
Spain	Hospital San Pedro de Alcantara	Caceres
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario HM Madrid Sanchinarro	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	MD Anderson Cancer Centre	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocio	Seville
Spain	Oncologia	Valencia
Switzerland	Inselspital - Universitaetsspital Bern	Bern
United Kingdom	Royal Bournemouth General Hospital	Bournemouth
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West Of Scotland Cancer Centre	Glasgow
United Kingdom	St. James's University Hospital	Leeds
United Kingdom	Guy's Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	Christie Hospital NHS Foundation Trust	Manchester
United States	Mission Hospital_ Cancer Care of Western North Carolina	Asheville	North Carolina
United States	Associates in Oncology & Hematology, PC	Bethesda	Maryland
United States	Boca Raton Community Hospital	Boca Raton	Florida
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital- MGH	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Rosewell Park Cancer Institute	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Oncology Hematology Care	Cincinnati	Ohio
United States	Texas Oncology, P.A.	Dallas	Texas
United States	Karmanos Cancer Center	Detroit	Michigan
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Texas Oncology PA	Fort Worth	Texas
United States	Hackensack Medical Center	Hackensack	New Jersey
United States	Broome Oncology	Johnson City	New York
United States	Joliet Oncology - Hematology Associates	Joliet	Illinois
United States	Texas Oncology PA - McAllen	McAllen	Texas
United States	University of Miami	Miami	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	SCRI - Tennessee Oncology	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College New York Presbyterian Hospital	New York	New York
United States	GU Research Network	Omaha	Nebraska
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	Health Midwest Ventures Group, Inc d/b/a HCA MidAmerica Division, LLC	Overland Park	Kansas
United States	Texas Oncology PA - Paris	Paris	Texas
United States	Florida Cancer Specialists ( North Region)	Saint Petersburg	Florida
United States	Stanford School of Medicine	Stanford	California
United States	USOR Texas Oncology	The Woodlands	Texas
United States	Healthcare Research Network III, LLC	Tinley Park	Illinois
United States	Cotton-Oneil Clinical Research Center	Topeka	Kansas
United States	Texas Oncology PA - Tyler	Tyler	Texas
United States	Florida Cancer Specialists	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Greece,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) by Independent Imaging Review (IIR)	PFS assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurred first) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.	From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)
Secondary	Objective Response Rate (ORR)	ORR is defined as the proportion of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1. CR is defined as disappearance of all (targeted and non-target [NT]) lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Overall Survival (OS)	OS is defined as the time from the date of randomization to the date of death from any cause. Participants who were lost to follow-up and those who were alive at the data cutoff date were censored, either at the last date the participant was last known alive or at the data cutoff date, whichever occurred first. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug.An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Number of Participants Who Discontinued Treatment Due to Toxicity	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Time to Treatment Failure Due to Toxicity	Time to treatment failure due to toxicity is defined as time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores	The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score	EORTC QLQ-C30 is a questionnaire including 30 questions that rate the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. For the overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score	EQ-5D-3L is a health profile questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analog scale (EQ-VAS). For the EQ-5D, participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at 1 of 3 levels (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 (full health) to <0 (worse health/dead). The EQ-VAS measures self-rated global health status using a vertically oriented VAS, where 100 represents the "best imaginable health state" and 0 represents the "worst imaginable health state." Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	PFS on Next-line of Therapy (PFS2)	PFS2 is defined as the time from randomization to disease progression as assessed by investigator on next-line treatment or death from any cause (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	PFS by Investigator Assessment	PFS by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST 1.1 or death (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Up to approximately 69 months
Secondary	Model-predicted Clearance for Lenvatinib and Everolimus	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length=21 days)
Secondary	Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2024).	Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length = 21 days