Clinical trial NCT03173560: Trial to Assess Safety and Efficacy of Lenvatinib (18 mg vs. 14 mg) in Combination With Everolimus in Participants With Renal Cell Carcinoma
Official title: A Randomized, Open-Label (Formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Keywords: Renal Cell Carcinoma
lenvatinib
everolimus
E7080
VEGF-targeted treatment
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-06-02
Enrollment: 343
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Objective Response Rate at Week 24 (ORR24W)
timeFrame: At Week 24
measure: Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks
timeFrame: Up to Week 24
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to date of data cutoff for the primary analysis (up to 29 months)
measure: Objective Response Rate (ORR)
timeFrame: From date of randomization up to first documentation of PD or date of death, whichever occurred first or up to the date of data cut off for the primary analysis (up to 29 months)
measure: Number of Participants With TEAEs and Serious TEAEs
timeFrame: From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)
measure: Percentage of Participants Who Discontinued Treatment Due to Toxicity
timeFrame: From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)
measure: Time to Treatment Failure Due to Toxicity
timeFrame: From the date of randomization to the date of discontinuation of study treatment due to TEAEs, or date of data cut off for the primary analysis (up to 29 months)
measure: Plasma Concentration of Lenvatinib
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Whole Blood Concentration of Everolimus
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib Alone and When Coadministration With Everolimus in Renal Cell Carcinoma (RCC) Participants to Assess Drug-Drug Interaction
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Model Predicted Dose Normalized Area Under the Plasma Concentration-time Curve (AUC) for Lenvatinib Alone and When Coadministration With Everolimus in RCC Participants to Assess Drug-Drug Interaction
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Model Predicted CL/F for Everolimus Alone and When Coadministration With Lenvatinib in RCC Participants to Assess Drug-Drug Interaction
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Model Predicted Dose Normalized AUC for Everolimus Alone and When Coadministration With Lenvatinib in RCC Participants to Assess Drug-Drug Interaction
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
measure: Overall Survival (OS)
timeFrame: From the date of randomization until the date of death from any cause, or up to date of data cut off for the primary analysis (up to 29 months)
measure: Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores
timeFrame: At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
measure: HRQoL Assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Scores
timeFrame: At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
measure: HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)
timeFrame: At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
measure: Progression-free Survival After Next Line of Therapy (PFS2)
timeFrame: From the time of randomization to the date of PD after next line of therapy or death from any cause or the date of data cutoff for the primary analysis, whichever occurs first (up to 29 months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute, LLC
state: California
city: Miami
country: United States
facility: Baptist Health Medical Group Oncology, LLC - US Oncology
state: Florida
city: Honolulu
country: United States
facility: Optimal Research
state: Hawaii
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialist and Research Institute , LLC
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Oncology PA - US Oncology
state: Texas
city: Macquarie Park
country: Australia
facility: Macquarie University
state: New South Wales
city: Saint Leonards
country: Australia
facility: Northern Cancer Institute, Saint Leonards
state: New South Wales
city: Kurralta Park
country: Australia
facility: Adelaide Cancer Center
state: South Australia
city: Saint Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Alberta Health Service - Tom Baker Cancer Centre
state: Alberta
city: Kelowna
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute- University of Toronto
state: Ontario
city: Montreal
country: Canada
facility: Sir Mortimer B Davis Jewish General Hospital
state: Quebec
city: Brno
country: Czechia
facility: Masarykuv onkologicky ustav
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Prague
country: Czechia
facility: Fakultni nemocnice v Motole
city: Prague
country: Czechia
facility: Nemocnice Na Bulovce
city: Helsinki
country: Finland
facility: Helsingin Yliopistollinen Keskussairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Turku
country: Finland
facility: Turun Yliopistollinen Keskussairaala
city: Vaasa
country: Finland
facility: Vaasan Keskussairaala
city: Athens
country: Greece
facility: Alexandra Hospital
city: Athens
country: Greece
facility: Metropolitan hospital
city: Patras
country: Greece
facility: University General Hospital of Patras
city: Pylaia
country: Greece
facility: Interbalkan Medical Center of Thessaloniki
city: Thessaloniki
country: Greece
facility: EUROMEDICA General Clinic of Thessaloniki
city: Thessaloniki
country: Greece
facility: Papageorgiou General Hospital of Thessaloniki
city: Milano
country: Italy
facility: IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Arezzo
country: Italy
facility: Presidio Ospedaliero San Donato
city: Napoli
country: Italy
facility: AORN A Cardarelli
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggido
city: Chŏnam
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital - Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul Saint Mary's Hospital
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
city: Den Haag
country: Netherlands
facility: MC Haaglanden
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Brzozow
country: Poland
facility: Szpital Specjalistyczny w Brzozowie
city: Gdansk
country: Poland
facility: Copernicus PL Sp. z o.o. Wojewodzkie Centrum Onkologii
city: Krakow
country: Poland
facility: NZOZ Vesalius
city: Krakow
country: Poland
facility: SP ZOZ Szpital Uniwersytecki w Krakowie
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej
city: Opole
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Opolskie Centrum Onkologii
city: Rzeszow
country: Poland
facility: Mrukmed. Lekarz Beata Madej-Mruk i Partner. Spolka Partnerska
city: Warszawa
country: Poland
facility: MAGODENT Sp. z o.o. Szpital Elblaska
city: Coimbra
country: Portugal
facility: Centro Hospitalar E Universitário de Coimbra EPE
city: Lisboa
country: Portugal
facility: Champalimaud Cancer Center
city: Lisbon
country: Portugal
facility: Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto - Hospital de Santo António
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe
city: Cluj-Napoca
country: Romania
facility: Medisprof SRL
city: Cluj-Napoca
country: Romania
facility: Prof Dr I Chiricuta Institute of Oncology
city: Craiova
country: Romania
facility: Oncology Center Sfantul Nectarie
city: Timisoara
country: Romania
facility: Oncocenter Clinical Oncology
city: Barnaul
country: Russian Federation
facility: Altay Regional Oncology Center
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk Regional Clinical Oncology Dispensary
city: Moscow
country: Russian Federation
facility: Central Clinical Hospital With Polyclinic of President Administration of RF
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital #62
city: Moscow
country: Russian Federation
facility: Moscow Scientific Research Oncology Institute P.A. Herzen
city: Obninsk
country: Russian Federation
facility: Federal State Institution Medical Radiology Research Center
city: Omsk
country: Russian Federation
facility: Clinical Oncology Dispensary
city: Yaroslavl
country: Russian Federation
facility: Regional Clinical Oncology Hospital
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruna
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau
city: Cordoba
country: Spain
facility: C.H. Regional Reina Sofia
city: Hospitalet de Llobregat
country: Spain
facility: ICO l'Hospitalet - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Pamplona
country: Spain
facility: Clinica Universidad Navarra
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Northwood
country: United Kingdom
facility: Mount Vernon Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
Study officials:
References:
citation: 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.