Hepatocellular Carcinoma (HCC)Phase 3NCT01761266
A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-line Treatment of Participants With Unresectable Hepatocellular Carcinoma
A Phase 3 study testing Lenvatinib and Sorafenib in people with Hepatocellular Carcinoma (HCC), run by Eisai Limited at 186 sites in 21 countries.
Trial summary
E7080-G000-304 is a multicenter, randomized, open-label, noninferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in participants with unresectable Hepatocellular Carcinoma (HCC). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma (HCC)
- What is being tested?
- Lenvatinib and Sorafenib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 954 participants
- Where
- 186 sitesin 21 countries
- Study dates
- 1 Mar 2013to 10 Mar 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- Imaging findings for HCC corresponding to any of the following:
- HCC with >=50 percent liver occupation
- Clear invasion into the bile duct
- Portal vein invasion at the main portal branch (Vp4).
- Participants who have received any systemic chemotherapy, including anti-vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agents, including lenvatinib, for advanced/unresectable HCC. Note: Participants who have received local hepatic injection chemotherapy are eligible.
- Participants who have received any anticancer therapy (including surgery, percutaneous ethanol injection, radio frequency ablation, transarterial [chemo] embolization, hepatic intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or any blood enhancing treatment (including blood transfusion, blood products, or agents that stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) within 28 days prior to randomization.
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- Participants who have not recovered from toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as < Grade 2 severity per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
- Significant cardiovascular impairment: history of congestive heart failure > New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
- Prolongation of corrected QT interval (QTc) interval to >480 millisecond (ms)
- Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib in the opinion of the investigator.
- Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low molecular weight heparin and factor X inhibitors which do not require INR monitoring is permitted. Antiplatelet agents are prohibited throughout the study.
- Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 28 days prior to randomization.
- Gastric or esophageal varices that require interventional treatment within 28 days prior to randomization. Prophylaxis with pharmacologic therapy (eg, nonselective beta-blocker) is permitted.
- Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 36 months.
- Participants whose only target lesion(s) is in bone will be excluded.
- Meningeal carcinomatosis.
- Any history of or current brain or subdural metastases.
- Participants having >1+ proteinuria on urine dipstick testing will undergo a 24-hour urine collection for quantitative assessment of proteinuria. Participants with a urine protein >=1g/24 hours will be ineligible.
- Surgical arterial-portal venous shunt or arterial-venous shunt.
- Any medical or other condition that in the opinion of the investigator would preclude the participant's participation in a clinical study.
- Known intolerance to lenvatinib or sorafenib (or any of the excipients).
- Human immunodeficiency virus (HIV) positive or active infection requiring treatment (except for hepatitis virus).
- Any history of drug or alcohol dependency or abuse within the prior 6 months.
- Any participant who cannot be evaluated by either triphasic liver computed tomography (CT) or triphasic liver Magnetic resonance imaging (MRI) because of allergy or other contraindication to both CT and MRI contrast agents.
- Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study.
- Participants has had a liver transplant.
Trial locations and contacts
186 sites in 21 countries.
186 sites in 21 countries
Japan25 sites
Facility # 1
Bunkyo-Ku, Tokyo
Facility # 1
Chuo-ku, Tokyo
Facility # 1
Fukuoka
Facility # 1
Hiroshima
Facility # 1
Kanazawa, Ishikawa-ken
Facility # 1
Kashiwa, Chiba
Facility # 1
Kawasaki, Kanagawa
Facility # 1
Koto-ku, Tokyo
Facility # 1
Kurume, Fukuoka
Facility # 1
Matsuyama, Ehime
Facility # 1
Minato-ku, Tokyo
Facility # 1
Musashino, Tokyo
Facility # 1
Nagoya, Aichi-ken
Facility # 1
Nishinomiya, Hyōgo
Facility # 1
Okayama
Facility # 1
Ōmura, Nagasaki
Facility # 2
Osaka
Facility # 1
Ōsaka-sayama, Osaka
Facility # 1
Saga
Facility # 2
Saga
Facility # 1
Sapporo, Hokkaido
Facility # 2
Sapporo, Hokkaido
Facility # 1
Shimonoseki, Yamaguchi
Facility # 1
Tsu, Mie-ken
Facility # 1
Yokohama, Kanagawa
United States21 sites
Facility # 1
Austin, Texas
Facility # 1
Baltimore, Maryland
Facility # 1
Brooklyn, New York
Facility # 1
Charlotte, North Carolina
Facility # 1
Detroit, Michigan
Facility # 1
Duluth, Georgia
Facility # 1
Durham, North Carolina
Facility # 1
East Orange, New Jersey
Facility # 1
Kansas City, Missouri
Facility # 1
Lake Success, New York
Facility # 1
Lawrenceville, Georgia
Facility # 1
Los Angeles, California
Facility # 1
Lubbock, Texas
Facility # 1
New York, New York
Facility # 1
Portland, Oregon
Facility # 1
Sacramento, California
Facility # 1
San Francisco, California
Facility # 1
Seattle, Washington
Facility # 1
St Louis, Missouri
Facility # 1
Tampa, Florida
Facility # 1
Washington D.C., District of Columbia
China21 sites
Facility # 1
Beijing, Beijing Municipality
Facility # 2
Beijing, Beijing Municipality
Facility # 3
Beijing, Beijing Municipality
Facility # 1
Changchun, Jilin
Facility # 1
Changsha, Hunan
Facility # 1
Chongqing, Chongqing Municipality
Facility # 1
Dalian, Liaoning
Facility # 1
Fuzhou, Fujian
Facility # 2
Fuzhou, Fujian
Facility # 1
Guangzhou, Guangdong
Facility # 1
Hangzhou, Zhejiang
Facility # 1
Harbin, Heilongjiang
Facility # 1
Hefei, Anhui
Facility # 1
Jinan, Shandong
Facility # 1
Nanjing, Jiangsu
Facility # 1
Shanghai, Shanghai Municipality
Facility # 3
Shanghai, Shanghai Municipality
Facility # 1
Suzhou, Jiangsu
Facility # 1
Tianjin, Zhejiang
Facility # 1
Xi’an, Shanxi
Facility # 2
Xi’an, Shanxi
South Korea18 sites
Facility # 1
Busan
Facility # 2
Busan
Facility # 3
Busan
Facility # 1
Daegu, Gyeongsangbuk-do
Facility # 1
Goyang-si, Gyeonggi-do
Facility # 1
Hwasun, Jeollanam-do
Facility # 1
Incheon
Facility # 1
Seongnam-si, Gyeonggi-do
Facility # 2
Seongnam-si, Gyeonggi-do
Facility # 1
Seoul
Facility # 2
Seoul
Facility # 3
Seoul
Facility # 4
Seoul
Facility # 5
Seoul
Facility # 6
Seoul
Facility # 7
Seoul
Facility # 8
Seoul
Facility # 1
Suwon, Gyeonggi-do
France15 sites
Facility # 1
Amiens, Somme
Facility # 1
Bordeaux
Facility # 1
Créteil, Val De Marne
Facility # 1
Lille
Facility # 1
Lyon
Facility # 1
Montpellier, Herault
Facility # 1
Nice, Alpes Maritimes
Facility # 1
Nord, 59037
Facility # 1
Paris, 75013
Facility # 1
Paris, 75020
Facility # 1
Pessac, Gironde
Facility # 1
Rennes, Ille Et Vilaine
Facility # 1
Rhone
Facility # 1
Toulouse, Haute Garonne
Facility # 1
Vandœuvre-lès-Nancy, Meurthe Et Moselle
Taiwan12 sites
Facility # 1
Kaohsiung City
Facility # 2
Kaohsiung City
Facility # 1
Taichung
Facility # 2
Taichung
Facility # 1
Tainan
Facility # 2
Tainan
Facility # 1
Taipei
Facility # 2
Taipei
Facility # 3
Taipei
Facility # 4
Taipei
Facility # 5
Taipei
Facility # 1
Taoyuan City
Italy8 sites
Facility # 1
Bari
Facility # 1
Benevento
Facility # 1
Bologna
Facility # 1
Naples
Facility # 2
Naples
Facility # 1
Palermo
Facility # 1
Roma
Facility # 1
Torrette, Ancona
Spain8 sites
Facility # 1
Badajoz
Facility # 1
Girona
Facility # 1
L'Hospitalet de Llobregat, Barcelona
Facility # 1
Madrid
Facility # 2
Madrid
Facility # 3
Madrid
Facility # 4
Madrid
Facility # 1
Santander, Cantabria
Australia7 sites
Facility # 1
Camperdown, New South Wales
Facility # 1
Fitzroy, Victoria
Facility # 1
Melbourne, Victoria
Facility # 2
Melbourne, Victoria
Facility # 1
Nedlands, Western Australia
Facility # 1
Wentworthville, New South Wales
Facility # 1
Woolloongabba, Queensland
Germany7 sites
Facility # 1
Cologne, North Rhine-Westphalia
Facility # 1
Essen, North Rhine-Westphalia
Facility # 1
Hanover, Lower Saxony
Facility # 1
Heidelberg, Baden-Wurttemberg
Facility # 1
Mainz, Rhineland-Palatinate
Facility # 1
Marburg, Hesse
Facility # 1
Tübingen, Baden-Wurttemberg
United Kingdom7 sites
Facility # 1
Birmingham, West Midlands
Facility # 1
Glasgow, Strathclyde
Facility # 1
Liverpool, Merseyside
Facility # 2
London, Greater London, W12 OHS
Facility # 1
London, Greater London
Facility # 3
London, Greater London
Facility # 1
Manchester, Greater Manchester
Russia6 sites
Facility # 1
Arkhangelsk
Facility # 1
Moscow
Facility # 2
Moscow
Facility # 3
Saint Petersburg
Facility # 4
Saint Petersburg
Facility # 1
Ufa
Malaysia5 sites
Facility # 1
Batu Caves, Selangor
Facility # 1
George Town, Pulau Pinang
Facility # 1
Kuala Lumpur
Facility # 1
Kuantan, Pahang
Facility # 1
Miri, Sarawak
Philippines5 sites
Facility # 1
Cebu City
Facility # 2
Cebu City
Facility # 1
Davao City
Facility # 1
Quezon City
Facility # 2
Quezon City
Thailand5 sites
Facility # 1
Bangkoknoi, Bangkok
Facility # 1
Muang, Changwat Chiang Rai
Facility # 1
Muang, Chiang Mai
Facility # 1
Pathum Wan, Bangkok
Facility # 1
Ratchathewi, Bangkok
Hong Kong4 sites
Facility # 1
Hong Kong
Facility # 2
Hong Kong
Facility # 3
Hong Kong
Facility # 1
Kowloon
Singapore4 sites
Facility # 1
Singapore
Facility # 2
Singapore
Facility # 3
Singapore
Facility # 4
Singapore
About this study
Official title: A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma
E7080-G000-304 is a multicenter, randomized, open-label, noninferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in participants with unresectable Hepatocellular Carcinoma (HCC).
- Conditions
- Hepatocellular Carcinoma (HCC)
- Being tested
- Lenvatinib, Sorafenib
- Keywords
- Hepatocellular Carcinoma, Neoplasms, Cancer
- Medical subject headings
- Carcinoma, Hepatocellular, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LenvatinibDrug
Also called E7080, Lenvima
12 mg (or 8 mg) once daily (QD) oral dosing.
SorafenibDrug
400 mg twice daily (BID) oral dosing.
| Study group | Role | What they receive |
|---|---|---|
| Lenvatinib | Active comparator | Participants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent. Receives: Drug: Lenvatinib |
| Sorafenib | Active comparator | Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent. Receives: Drug: Sorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival (OS)
OS was defined as the duration from the date of randomization until the date of death from any cause. Participants who were lost to follow-up were censored at the last date the participant was known to be alive, and participants who remained alive were censored at the time of data cutoff.
Measured: From date of randomization until date of death from any cause (approximately up to 3.8 years)
Secondary outcomes (7)
Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of first documentation of disease progression based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), or date of death, whichever occurred first. Disease progression was defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)
Time to Progression (TTP)
TTP was defined as the time from the date of randomization to the date of first documentation of disease progression based on mRECIST. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: The time from the date of randomization to the date of first documentation of disease progression (approximately up to 3.8 years)
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) based on mRECIST. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference to the baseline sum of the diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of Health Related Quality of Life (HRQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
The EORTC QLQ-C30 included 30 questions comprising 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social) and 9 symptom scales (fatigue, pain, nausea/vomiting, dyspnoea, appetite loss, insomnia, constipation, diarrhea and financial difficulties) and a single global health and QOL status score. Most questions used a 4-point scale (1=Not at all to 4=Very much); 2 questions used a 7-point scale (1= Very poor to 7=Excellent). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18)
The EORTC QLQ-HCC-18 was an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30. EORTC QLQ-HCC 18 questionnaire included 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. Each individual item ranges from 1 to 4, where 1 = "not at all" and 4 = "very much." All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represented a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represented a high QoL, but a high score for a symptom scale/item represented a high level of symptomatology/problem. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of HRQoL Assessed Using EuroQol Five Dimension Health Questionnaire (EQ-5D-3L)
The EuroQol five dimension health questionnaire (EQ-5D-3L) assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). EQ-5D-3L also included an EQ health utilities index (HUI) where 1.00 indicated perfect health while a score of 0.00 indicated death. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib
AUC was assessed on Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 1 Day 15. Summarized data for all time points was reported. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.
Measured: Cycle 1 Day 1, Cycle 2 Day 1: pre-dose, 0.5-4 and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 2-12 hours post-dose (cycle length= 28 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jan 2013 (estimated)
- Study start1 Mar 2013
- Primary completion13 Nov 2016
- Study completion10 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Hepatocellular Carcinoma (HCC)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 954 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eisai Limited
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01761266
- Sponsor's protocol ID
- E7080-G000-304
- Other IDs
- 2012-002992-33
- Status last verified
- Mar 2022
- First submitted
- 2 Jan 2013
- Last updated
- 5 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, Ryoo BY, Mody K, Ren M, Ramji Z, Sung MW. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer. 2024 Apr 15;130(8):1281-1291. doi: 10.1002/cncr.35185. Epub 2024 Jan 23.
PubMed 38261521Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Vogel A, Tovoli F, Ueshima K, Aikata H, Lopez CL, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Tamai T, Saito K, Dutcus CE, Lencioni R. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol. 2023 Jan;78(1):133-141. doi: 10.1016/j.jhep.2022.09.006. Epub 2022 Sep 20.
PubMed 36341767Huynh J, Cho MT, Kim EJ, Ren M, Ramji Z, Vogel A. Lenvatinib in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function. Ther Adv Med Oncol. 2022 Aug 24;14:17588359221116608. doi: 10.1177/17588359221116608. eCollection 2022.
PubMed 36051472Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, Yoon JH, Fartoux L, Simon K, Lopez C, Sung M, Mody K, Ohtsuka T, Tamai T, Bennett L, Meier G, Breder V. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):649-658. doi: 10.1016/S2468-1253(21)00110-2. Epub 2021 Jun 2.
PubMed 34087115Okusaka T, Ikeda K, Kudo M, Finn R, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrwicz L, Yoon JH, Ren Z, Mody K, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H. Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT. J Gastroenterol. 2021 Jun;56(6):570-580. doi: 10.1007/s00535-021-01785-0. Epub 2021 May 4.
PubMed 33948712Briggs A, Daniele B, Dick K, Evans TRJ, Galle PR, Hubner RA, Lopez C, Siebert U, Tremblay G. Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma. Br J Cancer. 2020 Jun;122(12):1754-1759. doi: 10.1038/s41416-020-0817-7. Epub 2020 Apr 8.
PubMed 32265508Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, Aikata H, Kawaguchi Y, Wada Y, Numata K, Inaba Y, Kuromatsu R, Kobayashi M, Okusaka T, Tamai T, Kitamura C, Saito K, Haruna K, Okita K, Kumada H. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020 Jan;55(1):113-122. doi: 10.1007/s00535-019-01642-1. Epub 2019 Nov 12.
PubMed 31720835Evans TRJ, Kudo M, Finn RS, Han KH, Cheng AL, Ikeda M, Kraljevic S, Ren M, Dutcus CE, Piscaglia F, Sung MW. Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma. Br J Cancer. 2019 Jul;121(3):218-221. doi: 10.1038/s41416-019-0506-6. Epub 2019 Jun 28.
PubMed 31249394Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
PubMed 29433850
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma
- ClinicalTrials.gov ID
- NCT01761266
- Acronym / sponsor ID
- E7080-G000-304
- Conditions
- Hepatocellular Carcinoma (HCC)
- Keywords
- Hepatocellular Carcinoma, Neoplasms, Cancer
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 954 participants (actual)
- Lead sponsor
- Eisai LimitedIndustry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 1 Mar 2013 (actual)
- Primary completion
- 13 Nov 2016 (actual)
- Study completion
- 10 Mar 2021 (actual)
- First posted
- 4 Jan 2013 (estimated)
- Results
- Posted 25 Sep 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
E7080-G000-304 is a multicenter, randomized, open-label, noninferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in participants with unresectable Hepatocellular Carcinoma (HCC).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lenvatinib | Active comparator | Drug: LenvatinibParticipants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent. |
| Sorafenib | Active comparator | Drug: SorafenibParticipants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (26 listed)
- Imaging findings for HCC corresponding to any of the following:
- Participants who have received any systemic chemotherapy, including anti-vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agents, including lenvatinib, for advanced/unresectable HCC. Note: Participants who have received local hepatic injection chemotherapy are eligible.
- Participants who have received any anticancer therapy (including surgery, percutaneous ethanol injection, radio frequency ablation, transarterial [chemo] embolization, hepatic intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or any blood enhancing treatment (including blood transfusion, blood products, or agents that stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) within 28 days prior to randomization.
- Participants who have not recovered from toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as < Grade 2 severity per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
- Significant cardiovascular impairment: history of congestive heart failure > New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LenvatinibAlso: E7080, Lenvima12 mg (or 8 mg) once daily (QD) oral dosing. | Drug | Lenvatinib |
| Sorafenib400 mg twice daily (BID) oral dosing. | Drug | Sorafenib |
Primary outcome
Overall Survival (OS)
Time frame: From date of randomization until date of death from any cause (approximately up to 3.8 years)
OS was defined as the duration from the date of randomization until the date of death from any cause. Participants who were lost to follow-up were censored at the last date the participant was known to be alive, and participants who remained alive were censored at the time of data cutoff.
7 secondary outcomes
Progression Free Survival (PFS)
Time frame: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)
Time to Progression (TTP)
Time frame: The time from the date of randomization to the date of first documentation of disease progression (approximately up to 3.8 years)
Objective Response Rate (ORR)
Time frame: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of Health Related Quality of Life (HRQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
Time frame: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18)
Time frame: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Time to Clinically Meaningful Worsening of HRQoL Assessed Using EuroQol Five Dimension Health Questionnaire (EQ-5D-3L)
Time frame: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)
Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib
Time frame: Cycle 1 Day 1, Cycle 2 Day 1: pre-dose, 0.5-4 and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 2-12 hours post-dose (cycle length= 28 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38261521Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, Ryoo BY, Mody K, Ren M, Ramji Z, Sung MW. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer. 2024 Apr 15;130(8):1281-1291. doi: 10.1002/cncr.35185. Epub 2024 Jan 23.
- Derived from this study: PubMed 36341767Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Vogel A, Tovoli F, Ueshima K, Aikata H, Lopez CL, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Tamai T, Saito K, Dutcus CE, Lencioni R. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol. 2023 Jan;78(1):133-141. doi: 10.1016/j.jhep.2022.09.006. Epub 2022 Sep 20.
- Derived from this study: PubMed 36051472Huynh J, Cho MT, Kim EJ, Ren M, Ramji Z, Vogel A. Lenvatinib in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function. Ther Adv Med Oncol. 2022 Aug 24;14:17588359221116608. doi: 10.1177/17588359221116608. eCollection 2022.
- Derived from this study: PubMed 34087115Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, Yoon JH, Fartoux L, Simon K, Lopez C, Sung M, Mody K, Ohtsuka T, Tamai T, Bennett L, Meier G, Breder V. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):649-658. doi: 10.1016/S2468-1253(21)00110-2. Epub 2021 Jun 2.
- Derived from this study: PubMed 33948712Okusaka T, Ikeda K, Kudo M, Finn R, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrwicz L, Yoon JH, Ren Z, Mody K, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H. Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT. J Gastroenterol. 2021 Jun;56(6):570-580. doi: 10.1007/s00535-021-01785-0. Epub 2021 May 4.
- Derived from this study: PubMed 32265508Briggs A, Daniele B, Dick K, Evans TRJ, Galle PR, Hubner RA, Lopez C, Siebert U, Tremblay G. Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma. Br J Cancer. 2020 Jun;122(12):1754-1759. doi: 10.1038/s41416-020-0817-7. Epub 2020 Apr 8.
- Derived from this study: PubMed 31720835Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, Aikata H, Kawaguchi Y, Wada Y, Numata K, Inaba Y, Kuromatsu R, Kobayashi M, Okusaka T, Tamai T, Kitamura C, Saito K, Haruna K, Okita K, Kumada H. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020 Jan;55(1):113-122. doi: 10.1007/s00535-019-01642-1. Epub 2019 Nov 12.
- Derived from this study: PubMed 31249394Evans TRJ, Kudo M, Finn RS, Han KH, Cheng AL, Ikeda M, Kraljevic S, Ren M, Dutcus CE, Piscaglia F, Sung MW. Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma. Br J Cancer. 2019 Jul;121(3):218-221. doi: 10.1038/s41416-019-0506-6. Epub 2019 Jun 28.
- Derived from this study: PubMed 29433850Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
186 sites in 21 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Lenvatinib and Sorafenib in people with Hepatocellular Carcinoma (HCC), run by Eisai Limited at 186 sites in 21 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 186 sites in Japan, United States, China, South Korea, France and 16 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival (OS) (time frame: From date of randomization until date of death from any cause (approximately up to 3.8 years)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01761266, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2022.