Trial to Assess Safety and Efficacy of Lenvatinib (18 mg vs. 14 mg) in Combination With Everolimus in Participants With Renal Cell Carcinoma

NCT ID: NCT03173560

Last Updated: 2025-04-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 343 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-17
• Study Completion Date: 2024-06-20

Brief Summary

Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR] at 24 weeks [ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or any greater than or equal to (>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Conditions

Renal Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lenvatinib 14 mg plus everolimus 5 mg

Participants will receive oral lenvatinib 14 mg once daily (QD) plus oral everolimus 5 mg QD as the starting dose for Cycle 1. If there are no intolerable Grade 2 or any \>= Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2 or later (cycle length equal to \[=\] 28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.

Group Type: EXPERIMENTAL

lenvatinib

Intervention Type: DRUG

lenvatinib capsules.

everolimus

Intervention Type: DRUG

everolimus tablets.

Lenvatinib 18 mg plus everolimus 5 mg

Participants will receive oral lenvatinib 18 mg QD plus oral everolimus 5 mg QD as the starting dose in Cycle 1 or later (cycle length =28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.

Group Type: EXPERIMENTAL

lenvatinib

Intervention Type: DRUG

lenvatinib capsules.

everolimus

Intervention Type: DRUG

everolimus tablets.

Interventions

lenvatinib

lenvatinib capsules.

Intervention Type: DRUG

everolimus

everolimus tablets.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable)
• Documented evidence of advanced RCC
• One prior disease progression episode on or after vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) treatment in addition to 1 prior VEGF-targeted treatment is allowed.
• At least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) meeting the following criteria:

• Lymph node (LN) lesion that measures at least 1 dimension as >=1.5 centimeter (cm) in the short axis;
• Non-nodal lesion that measures >=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.
• Male or female participants age >=18 years (or any age >=18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent
• Karnofsky Performance Status (KPS) of >=70
• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to (<=) 150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1
• Adequate renal function defined as calculated creatinine clearance >=30 milliliters per minute (mL/min) per the Cockcroft and Gault formula
• Adequate bone marrow function defined by:

• Absolute neutrophil count (ANC) >=1500/millimeters cubed (mm^3) (>=1.5*10^9/Liters [L]);
• Platelets >=100,000/mm^3 (>=100*10^9/L);
• Hemoglobin >=9 grams per deciliter (g/dL)
• Adequate blood coagulation function defined by International Normalized Ratio (INR) <=1.5 (except for participants on warfarin therapy where INR must be <=3.0 prior to randomization)
• Adequate liver function defined by:

• Total bilirubin <=1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome;
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3* the ULN (in the case of liver metastases <=5* the ULN). Participants with bone metastases with ALP values greater than 3 times can be included.
• Participant must voluntarily agree to provide written informed consent
• Participant must be willing and able to comply with all aspects of the protocol

Exclusion Criteria

• More than 1 prior VEGF-targeted treatment for advanced RCC
• Participants with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as <=10 mg prednisolone equivalent) before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
• Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months
• Any anti-cancer treatment (except for radiation therapy) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; participants should have recovered from any toxicity related to previous anti-cancer treatment to Common Toxicity Criteria (CTC) grade 0 or 1.
• Prior radiation therapy within 21 days prior to the 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
• Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (example, sirolimus, everolimus, temsirolimus) or any of the excipients
• Participants with proteinuria greater than (>) 1+ on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 hour will be ineligible.
• Fasting total cholesterol ˃300 mg/dL (or ˃7.75 millimoles [mmol]/L) and/or fasting triglycerides level ˃2.5* the ULN. Note: these participants can be included after initiation or adjustment of lipid-lowering medication.
• 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.
• Prolongation of QT corrected (QTc) interval to >480 milliseconds (ms)
• Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
• Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib or everolimus
• Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (example, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
• Significant cardiovascular impairment within 6 months prior to 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, or cardiac arrhythmia associated with significant cardiovascular impairment or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram.
• Active infection (any infection requiring systemic treatment)
• Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
• Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-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.
• Females of childbearing potential who (Note: 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 [that is, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing].):

• do not agree to use a highly effective method of contraception for the entire study period and for up to 8 weeks after study drug 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) (Note: Participants 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.) OR
• do not have a vasectomized partner with confirmed azoospermia

For sites outside of the European Union, 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Eisai Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

City of Hope National Medical Center

Duarte, California, United States

Innovative Clinical Research Institute, LLC

Whittier, California, United States

Baptist Health Medical Group Oncology, LLC - US Oncology

Miami, Florida, United States

Optimal Research

Honolulu, Hawaii, United States

Oklahoma Cancer Specialist and Research Institute , LLC

Tulsa, Oklahoma, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

University of Tennessee Medical Center

Knoxville, Tennessee, United States

Texas Oncology PA - US Oncology

Fort Worth, Texas, United States

Macquarie University

Macquarie Park, New South Wales, Australia

Northern Cancer Institute, Saint Leonards

Saint Leonards, New South Wales, Australia

Adelaide Cancer Center

Kurralta Park, South Australia, Australia

Sunshine Hospital

Saint Albans, Victoria, Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

Alberta Health Service - Tom Baker Cancer Centre

Calgary, Alberta, Canada

British Columbia Cancer Agency

Kelowna, British Columbia, Canada

Juravinski Cancer Centre

Hamilton, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

Ottawa Hospital Cancer Centre

Ottawa, Ontario, Canada

Sunnybrook Research Institute- University of Toronto

Toronto, Ontario, Canada

Sir Mortimer B Davis Jewish General Hospital

Montreal, Quebec, Canada

Masarykuv onkologicky ustav

Brno, , Czechia

Fakultni nemocnice Olomouc

Olomouc, , Czechia

Fakultni nemocnice v Motole

Prague, , Czechia

Nemocnice Na Bulovce

Prague, , Czechia

Helsingin Yliopistollinen Keskussairaala

Helsinki, , Finland

Tampereen yliopistollinen sairaala

Tampere, , Finland

Turun Yliopistollinen Keskussairaala

Turku, , Finland

Vaasan Keskussairaala

Vaasa, , Finland

Alexandra Hospital

Athens, , Greece

Metropolitan hospital

Athens, , Greece

University General Hospital of Patras

Pátrai, , Greece

Interbalkan Medical Center of Thessaloniki

Pylaia, , Greece

EUROMEDICA General Clinic of Thessaloniki

Thessaloniki, , Greece

Papageorgiou General Hospital of Thessaloniki

Thessaloniki, , Greece

IRCCS Istituto Nazionale dei Tumori

Milan, Lombardy, Italy

Presidio Ospedaliero San Donato

Arezzo, , Italy

AORN A Cardarelli

Napoli, , Italy

Azienda Ospedaliera San Camillo Forlanini

Roma, , Italy

Leids Universitair Medisch Centrum

Leiden, , Netherlands

Hagaziekenhuis

The Hague, , Netherlands

MC Haaglanden

The Hague, , Netherlands

Szpital Specjalistyczny w Brzozowie

Brzozów, , Poland

Copernicus PL Sp. z o.o. Wojewodzkie Centrum Onkologii

Gdansk, , Poland

NZOZ Vesalius

Krakow, , Poland

SP ZOZ Szpital Uniwersytecki w Krakowie

Krakow, , Poland

Centrum Onkologii Ziemi Lubelskiej

Lublin, , Poland

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Opolskie Centrum Onkologii

Opole, , Poland

Mrukmed. Lekarz Beata Madej-Mruk i Partner. Spolka Partnerska

Rzeszów, , Poland

MAGODENT Sp. z o.o. Szpital Elblaska

Warsaw, , Poland

Centro Hospitalar E Universitário de Coimbra EPE

Coimbra, , Portugal

Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria

Lisbon, , Portugal

Champalimaud Cancer Center

Lisbon, , Portugal

Centro Hospitalar do Porto - Hospital de Santo António

Porto, , Portugal

Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe

Porto, , Portugal

Medisprof SRL

Cluj-Napoca, , Romania

Prof Dr I Chiricuta Institute of Oncology

Cluj-Napoca, , Romania

Oncology Center Sfantul Nectarie

Craiova, , Romania

Oncocenter Clinical Oncology

Timișoara, , Romania

Altay Regional Oncology Center

Barnaul, , Russia

Chelyabinsk Regional Clinical Oncology Dispensary

Chelyabinsk, , Russia

Central Clinical Hospital With Polyclinic of President Administration of RF

Moscow, , Russia

Moscow City Oncology Hospital #62

Moscow, , Russia

Moscow Scientific Research Oncology Institute P.A. Herzen

Moscow, , Russia

Federal State Institution Medical Radiology Research Center

Obninsk, , Russia

Clinical Oncology Dispensary

Omsk, , Russia

Regional Clinical Oncology Hospital

Yaroslavl, , Russia

National Cancer Center

Goyang-si, Gyeonggido, South Korea

Chonnam National University Hwasun Hospital

Jeonam, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Severance Hospital - Yonsei University Health System

Seoul, , South Korea

The Catholic University of Korea, Seoul Saint Mary's Hospital

Seoul, , South Korea

Hospital Universitario A Coruna

A Coruña, , Spain

Hospital Universitario Germans Trias i Pujol

Badalona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital de la Santa Creu I Sant Pau

Barcelona, , Spain

C.H. Regional Reina Sofia

Córdoba, , Spain

ICO l'Hospitalet - Hospital Duran i Reynals

L'Hospitalet de Llobregat, , Spain

Hospital Clinico San Carlos

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

MD Anderson Cancer Center Madrid

Madrid, , Spain

Hospital Universitario Son Espases

Palma de Mallorca, , Spain

Clinica Universidad Navarra

Pamplona, , Spain

Fundacion Instituto Valenciano de Oncologia

Valencia, , Spain

China Medical University Hospital

Taichung, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Christie Hospital

Manchester, , United Kingdom

Mount Vernon Hospital

Northwood, , United Kingdom

Singleton Hospital

Swansea, , United Kingdom

Countries

United States; Australia; Canada; Czechia; Finland; Greece; Italy; Netherlands; Poland; Portugal; Romania; Russia; South Korea; Spain; Taiwan; United Kingdom

References

Bergerot C, Young Rha S, Pal S, Koralewski P, Stroyakovskiy D, Alekseev B, Parnis F, Castellano D, Lyun Lee J, Sunela K, Ciuleanu T, Heng D, Glen H, Wang J, Bennett L, Pan J, O'Hara K, Puente J. Health-Related Quality of Life Outcomes With Two Different Starting Doses of Lenvatinib in Combination With Everolimus for Previously Treated Renal Cell Carcinoma. Oncologist. 2023 Jan 18;28(1):59-71. doi: 10.1093/oncolo/oyac142.

Reference Type: DERIVED

PMID: 35881028 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002778-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E7080-G000-218

Identifier Type: -

Identifier Source: org_study_id