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

• ClinicalTrials.gov Identifier: NCT02811861
• Recruitment Status: Active, not recruiting
• First Posted: June 23, 2016
• Results First Posted: September 24, 2021
• Last Update Posted: July 10, 2023
• Sponsor: Eisai Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc.

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Renal Cell Carcinoma	Drug: Lenvatinib; Drug: Everolimus; Drug: Pembrolizumab; Drug: Sunitinib	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1069 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: October 13, 2016
• Actual Primary Completion Date: August 28, 2020
• Estimated Study Completion Date: July 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lenvatinib 18 mg plus Everolimus 5 mg; Lenvatinib 18 milligrams (mg) administered orally, once daily, plus everolimus 5 mg administered orally, once daily in each 21-day cycle.	Drug: Lenvatinib; Drug: Everolimus
Experimental: Lenvatinib 20 mg plus Pembrolizumab 200 mg; Lenvatinib 20 mg administered orally, once daily, in each 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV), every 3 weeks on Day 1 of each 21-day cycle.	Drug: Lenvatinib; Drug: Pembrolizumab
Active Comparator: Sunitinib 50 mg; Sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment in each 21-day cycle.	Drug: Sunitinib

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) by Independent Imaging Review (IIR) [ Time Frame: 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) ]
   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.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: Up to approximately 69 months ]
   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 2022).
2. Overall Survival (OS) [ Time Frame: Up to approximately 69 months ]
   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 2022).
3. Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 69 months ]
   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 2022).
4. Number of Participants Who Discontinued Treatment Due to Toxicity [ Time Frame: Up to approximately 69 months ]
   Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
5. Time to Treatment Failure Due to Toxicity [ Time Frame: Up to approximately 69 months ]
   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 2022).
6. Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores [ Time Frame: Up to approximately 69 months ]
   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 2022).
7. HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score [ Time Frame: Up to approximately 69 months ]
   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 2022).
8. HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score [ Time Frame: Up to approximately 69 months ]
   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 2022).
9. PFS on Next-line of Therapy (PFS2) [ Time Frame: Up to approximately 69 months ]
   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 2022).
10. PFS by Investigator Assessment [ Time Frame: Up to approximately 69 months ]
    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 2022).
11. Model-predicted Clearance for Lenvatinib and Everolimus [ Time Frame: 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) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
12. Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus [ Time Frame: 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 ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Stanford School of Medicine

Stanford, California, United States, 94305-5826

United States, Florida

Boca Raton Community Hospital

Boca Raton, Florida, United States, 33486

Florida Cancer Specialists

Fort Myers, Florida, United States, 33901

Mount Sinai Medical Center

Miami Beach, Florida, United States, 33136

University of Miami

Miami, Florida, United States, 33136

Florida Hospital Cancer Institute

Orlando, Florida, United States, 32804

Florida Cancer Specialists ( North Region)

Saint Petersburg, Florida, United States, 33705

Florida Cancer Specialists

West Palm Beach, Florida, United States, 33401

United States, Illinois

Joliet Oncology - Hematology Associates

Joliet, Illinois, United States, 60435

Healthcare Research Network III, LLC

Tinley Park, Illinois, United States, 60487

United States, Kansas

Health Midwest Ventures Group, Inc d/b/a HCA MidAmerica Division, LLC

Overland Park, Kansas, United States, 66209

Cotton-Oneil Clinical Research Center

Topeka, Kansas, United States, 66604

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Maryland

Associates in Oncology & Hematology, PC

Bethesda, Maryland, United States, 20817

United States, Massachusetts

Massachusetts General Hospital- MGH

Boston, Massachusetts, United States, 02214

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Center

Detroit, Michigan, United States, 48201

United States, Nebraska

GU Research Network

Omaha, Nebraska, United States, 68130

Nebraska Cancer Specialists

Omaha, Nebraska, United States, 68130

United States, New Jersey

Hackensack Medical Center

Hackensack, New Jersey, United States, 07601

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10461

Rosewell Park Cancer Institute

Buffalo, New York, United States, 14263

Broome Oncology

Johnson City, New York, United States, 13790

Weill Cornell Medical College New York Presbyterian Hospital

New York, New York, United States, 10021

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Mission Hospital_ Cancer Care of Western North Carolina

Asheville, North Carolina, United States, 28801

United States, Ohio

Oncology Hematology Care

Cincinnati, Ohio, United States, 45242

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29412

United States, Tennessee

SCRI - Tennessee Oncology

Nashville, Tennessee, United States, 37203

United States, Texas

Texas Oncology, P.A.

Dallas, Texas, United States, 75231

Texas Oncology PA

Fort Worth, Texas, United States, 76104

Texas Oncology PA - McAllen

McAllen, Texas, United States, 78503

Texas Oncology PA - Paris

Paris, Texas, United States, 75460

USOR Texas Oncology

The Woodlands, Texas, United States, 77380

Texas Oncology PA - Tyler

Tyler, Texas, United States, 75702

Australia, Victoria

Eastern Clinical Research Unit

Box Hill, Victoria, Australia, 3128

Austin Hospital

Heidelberg, Victoria, Australia, 3084

Australia

Royal Hobart Hospital

Hobart, Australia

Macquarie University Hospital

Macquarie park, Australia

ICON Cancer Foundation

South Brisbane, Australia

Sunshine Hospital

St Albans, Australia

Austria

Medizinische Universitat Innsbruck

Innsbruck, Austria

Krankenhaus der barmherzigen Schwestern Linz

Linz, Austria

AKH - Medizinische Universität Wien

Vienna, Austria, 1090

Belgium

O.L.V Ziekenhuis

Aalst, Belgium

ZNA Middelheim

Antwerpen, Belgium, 2260

Imeldaziekenhuis

Bonheiden, Belgium

Institut Jules Bordet

Bruxelles, Belgium, 1000

Jessa Ziekenhuis - Campus Virga Jesse

Hasselt, Belgium, 3500

Domaine Universitaire

Liege, Belgium, 4000

GZA Ziekenhuizen - Campus Sint-Augustinus

Wilrijk, Belgium, 2610

Canada, Alberta

Cross Cancer Institute

Edmonton, Alberta, Canada, T6G 1Z2

Canada, British Columbia

BC Cancer Agency Vancouver Centre

Vancouver, British Columbia, Canada, V5Z 1H7

Canada, Ontario

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada, L8N 4A6

London Institute of Health Sciences

London, Ontario, Canada, N6A4L6

Ottawa Hospital Cancer Centre

Ottawa, Ontario, Canada, K1H 8

Sunnybrook Research Institute - University of Toronto

Toronto, Ontario, Canada, M4N 3M5

Canada, Quebec

Centre de santé et de services sociaux Champlain-Charles-Le Moyne

Greenfield Park, Quebec, Canada, J4V 2H1

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, Czechia

France

ICO - Site Paul Papin

Angers, Maine Et Loire, France, 49055

Centre Georges François Leclerc

Dijon cedex, France, 21079

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 la Petie Salpetriere

Paris, France, cedex 13 75651

Hopital Europeen Georges Pompidou

Paris, France

Boulevard du Professeur Jacques Monod

Saint Herblain, France, 4805

CHU Strasbourg - Nouvel Hopital Civil

Strasbourg, France

Germany

EISAI Trial site 4

Stuttgart, Baden Wuerttemberg, Germany, 70174

EISAI Trial site 1

Tuebingen, Baden Wuerttemberg, Germany, 72076

EISAI Trial site 7

München, Bayern, Germany, 81377

EISAI Trial site 6

Frankfurt, Hessen, Germany, 60590

EISAI Trial site 14

Greifswald, Mecklenburg-Vorpommern, Germany

EISAI Trial site 8

Hannover, Niedersachsen, Germany, 30625

EISAI Trial site 13

Münster, Nordrhein Westfalen, Germany, 48149

EISAI Trial site 2

Homburg/Saar, Saarland, Germany, 66421

EISAI Trial site 5

Berlin, Germany, 12200

Greece

General Hospital of Athens "Alexandra"

Athens, Greece, 11528

University of Patras Medical School

Patras, Greece, 26504

General Hospital Papageorgiou

Thessaloníki, Greece, 56429

Interbalkan Hospital of Thessaloniki

Thessaloníki, Greece, 57001

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, Ireland

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, 49100

Chaim Sheba Medical Center

Ramat-Gan, Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel

Italy

Azienda Unità Sanitaria Locale- Ravenna

Faenza, Ravenna, Italy, 48018

Ospedale San Donato

Arezzo, Italy

Azienda Ospedaliera Universitaria Policlinico SantOrsola Malpighi

Bologna, Italy

Istituto Nazionale per la Ricerca sul Cancro di Genova

Genova, Italy, 16132

Presidio Ospedaliero Vito Fazzi

Lecce, Italy, 73100

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST

Meldola, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Milano, Italy, 20133

A.O.U. Policlinico di Modena

Modena, Italy, 41124

Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli

Napoli, Italy, 80131

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, 33170

Azienda Ospedaliera San Camillo Forlanini

Roma, Italy

Universita Campus Bio-Medico di Roma

Rome, Italy

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, Japan

Korea, Republic of

Kyungpook National University Chilgok Hospital

Daegu, Korea, Republic of, 41404

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, Korea, Republic of

Netherlands

Antoni van Leeuwenhoek

Amsterdam, Netherlands, 1066 CX

VU Medisch Centrum

Amsterdam, Netherlands, 1081 HV

UMC Utrecht

Utrecht, Netherlands, 3584 CX

Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland

Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie

Lublin, Poland

SPWSZ w Szczecinie im. Marii Sklodowskiej-Curie

Szczecin, Poland

Russian Federation

FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin - Department of Oncology

Moscow, Russian Federation, 115478

FSBI "Moscow scientific research oncology institute n.a. P.A. Gertsen" of MoH of RF

Moscow, Russian Federation, 125284

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, 630108

FSBI "National Medical Research Radiological Center" of the MoH of the RF

Obninsk, Russian Federation, 249036

BHI of Omsk region "Clinical Oncology Dispensary"

Omsk, Russian Federation, 644013

Spain

Hospital Universitario Marques de Valdecilla

Santander, Cantabria, Spain, 39008

Hospital Clinic i Provincial de Barcelona

Barcelona, Spain, 08036

ICO l'Hospitalet - Hospital Duran I Reynals

Barcelona, Spain, 08908

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Hospital San Pedro de Alcantara

Caceres, Spain, 10003

Hospital Universitario Reina Sofia

Cordoba, Spain

Hospital Universitario Ramon y Cajal

Madrid, Spain, 28034

Hospital General Universitario Gregorio Maranon

Madrid, Spain

Hospital Universitario Clinico San Carlos

Madrid, Spain

Hospital Universitario HM Madrid Sanchinarro

Madrid, Spain

MD Anderson Cancer Centre

Madrid, Spain

Hospital Universitario Central de Asturias

Oviedo, Spain, 33011

Hospital Universitario Virgen del Rocio

Seville, Spain

Oncologia

Valencia, Spain, 46009

Switzerland

Inselspital - Universitaetsspital Bern

Bern, Switzerland

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, G12 0YN

St. James's University Hospital

Leeds, United Kingdom, LS9 7TF

Guy's Hospital

London, United Kingdom

Royal Free Hospital

London, United Kingdom

Christie Hospital NHS Foundation Trust

Manchester, United Kingdom, M20 4BX

Sponsors and Collaborators

Eisai Inc.

Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Eisai Inc.:

Study Protocol  [PDF] August 6, 2020

Statistical Analysis Plan  [PDF] August 14, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Motzer R, Porta C, Alekseev B, Rha SY, Choueiri TK, Mendez-Vidal MJ, Hong SH, Kapoor A, Goh JC, Eto M, Bennett L, Wang J, Pan JJ, Saretsky TL, Perini RF, He CS, Mody K, Cella D. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022 Jun;23(6):768-780. doi: 10.1016/S1470-2045(22)00212-1. Epub 2022 Apr 27.

Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grunwald V, Hutson TE, Kopyltsov E, Mendez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. doi: 10.1056/NEJMoa2035716. Epub 2021 Feb 13.

Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT02811861
• Other Study ID Numbers: E7080-G000-307; KEYNOTE-581 ( Other Identifier: Merck ); 2016-000916-14 ( EudraCT Number )
• First Posted: June 23, 2016
• Results First Posted: September 24, 2021
• Last Update Posted: July 10, 2023
• Last Verified: July 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:

Renal Cell Carcinoma (RCC); Lenvatinib; First-line RCC; Treatment-naive RCC; Everolimus; Pembrolizumab; Sunitinib; Phase 3 RCC; Phase 3 first-line RCC; Phase 3 treatment-naive RCC

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Pembrolizumab; Everolimus; Sunitinib; Lenvatinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs