A Study of Atezolizumab With Lenvatinib or Sorafenib Versus Lenvatinib or Sorafenib Alone in Hepatocellular Carcinoma Previously Treated With Atezolizumab and Bevacizumab (IMbrave251)

A Phase III, Open-Label, Randomized Study of Atezolizumab With Lenvatinib or Sorafenib Versus Lenvatinib or Sorafenib Alone in Hepatocellular Carcinoma Previously Treated With Atezolizumab and Bevacizumab

This is a Phase III, open-label, multicenter, randomized, two-arm study designed to evaluate the efficacy and safety of atezolizumab plus either lenvatinib or sorafenib versus lenvatinib or sorafenib alone in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have progressed on prior systemic treatment with atezolizumab plus bevacizumab combination.

Study Overview

• Status: Active, not recruiting
• Conditions: Unresectable Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Atezolizumab; Drug: Lenvatinib; Drug: Sorafenib

• Study Type: Interventional
• Enrollment (Estimated): 554
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universität Innsbruck; Universitätsklinik für Innere Medizin I
  • Salzburg, Austria, 5020
    • Uniklinikum Salzburg, LKH; Univ.Klinik f. Innere Medizin III der PMU
  • St. Pölten, Austria, 3100
    • Universitätsklinikum St. Pölten; Innere Medizin 2
  • Wien, Austria, 1100
    • Klinik Favoriten; Abteilung für Chirurgie
• Belgium
  • Brasschaat, Belgium, 2930
    • AZ Klina
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires St-Luc
  • Bruxelles, Belgium, 1070
    • Hospital Erasme
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Roeselare, Belgium, 8800
    • AZ Delta (Campus Rumbeke)
• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30110-068
      • Hospital Felicio Rocho
  • RJ
    • Rio De Janeiro, RJ, Brazil, 22290-160
      • Clinicas Oncologicas Integradas - COI
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, RS, Brazil, 90035-000
      • Hospital Moinhos de Vento
  • SC
    • Florianopolis, SC, Brazil, 88020-210
      • YNOVA Pesquisa Clinica
  • SP
    • São Paulo, SP, Brazil, 01321-00
      • Beneficencia Portuguesa de Sao Paulo
• Bulgaria
  • Panagyurishte, Bulgaria, 4500
    • Multiprofile Hospital for Active Treatment Uni Hospital; Department of medicinal oncology
  • Plovdiv, Bulgaria, 4004
    • Complex Oncological Center - Plovdiv, EOOD; Second Internal Department
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre-Calgary
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Center
• Chile
  • Santiago, Chile, 7500653
    • Centro de Estudios Clínicos SAGA
• China
  • Beijing City, China, 100039
    • The Fifth Medical Center of People's Liberation Army General Hospital
  • Changsha CITY, China, 410013
    • Hunan Cancer Hospital
  • Fuzhou City, China, 350001
    • Fujian Provincial Hospital
  • Guangzhou, China, 510515
    • Nanfang Hospital, Southern Medical University
  • Guangzhou City, China, 510663
    • Sun Yet-sen University Cancer Center
  • Guangzhou City, China, 510080
    • The First Affiliated Hospital, Sun Yat-sen University
  • Hefei City, China, 230031
    • Anhui Province Cancer Hospital
  • Jinan, China, 250117
    • Shandong Cancer Hospital
  • Nanjing City, China, 210029
    • Jiangsu Province Hospital (the First Affiliated Hospital With Nanjing Medical University)
  • Shanghai, China, 200032
    • Zhongshan Hospital Fudan University
  • Shanghai, China, 200127
    • Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
  • ShenYang, China, 110004
    • Shengjing Hospital of China Medical University
  • Tianjin, China, 300060
    • Tianjin Cancer Hospital
• Costa Rica
  • San José, Costa Rica, 10103
    • Clinica CIMCA
  • San José, Costa Rica, 10108
    • ICIMED Instituto de Investigación en Ciencias Médicas
• Croatia
  • Zagreb, Croatia, 10000
    • Clinical Hospital Centre Zagreb
• Egypt
  • Cairo, Egypt, 11391
    • AirForce Specialized Hospital; Clinical Oncology
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonia Medical Centre, Oncology and hematology Clinic; Department of Chemotherapy
  • Tartu, Estonia, 50406
    • Tartu University Hospital; Clinic of Hematology and Oncology
• Finland
  • Tampere, Finland, 33521
    • TAYS Radius rakennus; onkologinen lääketutkimusyksikkö
• France
  • GRENOBLE Cedex 9, France, 38043
    • CHU Grenoble Sud; Service hépato-gastroentérologie
  • Lille, France, 59037
    • CHRU de Lille - Hopital Claude Huriez
  • Marseille, France, 13385
    • Aphm; Cpcet
  • Montpellier, France, 34295
    • CH Saint Eloi
  • Nantes, France, 44093
    • CHU de Nantes - Hôtel Dieu
  • Paris, France, 75571
    • APHP - Hopital Saint Antoine
  • Pessac, France, 33604
    • Chu Bordeaux
  • Rennes, France, 35042
    • Centre Eugene Marquis; Service d'oncologie; Direction de la Recherche Clinique
  • Toulouse Cedex 09, France, 31059
    • CHU de Toulouse - Hôpital Rangueil
  • Vandoeuvre-les-nancy, France, 54511
    • Hopitaux de Brabois - Gastro-Entereologie
  • Villejuif, France, 94804
    • Hopital Paul Brousse; Centre Hepatologie Biliaire
• Germany
  • Frankfurt, Germany, 60590
    • Klinik Johann Wolfgang von Goethe Uni; Zentrum der Inneren Medizin; Medizinische Klinik I
  • Hannover, Germany, 30625
    • Med. Hochschule Hannover; Gastroenterologie
  • Mainz, Germany, 55131
    • Uniklinik Mainz; I. Medizinische Klinik
  • Tübingen, Germany, 72076
    • Universität Tübingen; Med. Klinik; Innere Medizin I
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm; Zentrum für Innere Medizin Klinik für Innere Medizin I
• Greece
  • Athens, Greece, 115 27
    • Laiko General Hospital Athen; Uni Clinic of Gastrenterology
  • Nea Kifissia, Greece, 14564
    • Agioi Anargiroi Hospital of Kifissia; University Internal Medicine Clinic
• India
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • Tata Memorial Hospital; Dept of Medical Oncology
  • Telangana
    • Gachibowli, Telangana, India, 500032
      • AIG Hospitals
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus; Oncology
  • Petah Tikva, Israel, 4910000
    • Rabin Medical Center; Oncology Dept
  • Tel-Aviv, Israel, 6423900
    • Sourasky Medical Center; Oncology Department
• Italy
  • Campania
    • Napoli, Campania, Italy, 80100
      • Fondazione Pascale; U.O. Sperimentazioni Cliniche
    • Napoli, Campania, Italy, 80131
      • Azienda Osp Uni Seconda Università Degli Studi Di Napoli; Unità Operativa Oncologia Medica
    • Napoli, Campania, Italy, 80147
      • Ospedale del Mare; UOC di Oncologia
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O. S. Orsola Malpighi; Ambulatorio Epatocarcinoma (Bolondi)
  • Lazio
    • Roma, Lazio, Italy, 151
      • Azienda Ospedaliera San Camillo Forlanini
    • Rome, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Fondazione IRCCS Ospedale Maggiore Policlinico; Gastroenterologia
  • Piemonte
    • Torino, Piemonte, Italy, 10128
      • Azienda Ospedaliera Ordine Mauriziano di Torino
  • Sicilia
    • Palermo, Sicilia, Italy, 90100
      • A.O.U. Policlinico Paolo Giaccone; Gastroenterologia ed Epatologia
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1
    • Pisa, Toscana, Italy, 56100
      • Azlenda Ospendaliero-Universitaria Pisana; C.O. Oncologia 2
  • Veneto
    • Padova, Veneto, Italy, 35128
      • IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda
• Japan
  • Aichi, Japan, 470-1192
    • Fujita Health University Hospital
  • Chiba, Japan, 260-8677
    • Chiba University Hospital
  • Chiba, Japan, 277-8577
    • National Cancer Center Hospital East
  • Fukuoka, Japan, 830-0011
    • Kurume University Hospital
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital
  • Hyogo, Japan, 670-8540
    • Japanese Red Cross Society Himeji Hospital
  • Kanagawa, Japan, 232-0024
    • Yokohama City University Medical Center
  • Osaka, Japan, 565-0871
    • Osaka University Hospital
  • Osaka, Japan, 589-8511
    • Kindai University Hospital
  • Tochigi, Japan, 329-0498
    • Jichi Medical University Hospital
  • Tokyo, Japan, 180-8610
    • Japanese Red Cross Musashino Hospital
  • Tokyo, Japan, 105-8470
    • Toranomon Hospital
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center
  • Gyeonggi-do, Korea, Republic of, 13496
    • CHA Bundang Medical Center
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Malaysia
  • FED. Territory OF Kuala Lumpur
    • Kuala Lumpur, FED. Territory OF Kuala Lumpur, Malaysia, 59100
      • Uni Malaya Medical Center; Clinical Oncology Unit, Menara Timur
    • Putrajaya, FED. Territory OF Kuala Lumpur, Malaysia, 62250
      • Institute Kanser Negara (IKN)
  • Selangor
    • Petaling Jaya, Selangor, Selangor, Malaysia, 46050
      • Beacon International Specialist Centre; Clinical Research Department, Level 2
• Philippines
  • Cebu City, Philippines, 6000
    • Cebu Doctors' University Hospital; Research Office
  • Makati City, Philippines, 1229
    • Makati Medical Center
  • Pasig City, Philippines, 1600
    • The Medical City; Cancer Center
• Russian Federation
  • Moskovskaja Oblast
    • Moscow, Moskovskaja Oblast, Russian Federation, 115478
      • FSBI "National Medical Research Center of Oncology N.N. Blokhin?
    • Moscow, Moskovskaja Oblast, Russian Federation, 125134
      • Moscow City Oncology Hospital #62; Outpatient Care Center
    • Moskva, Moskovskaja Oblast, Russian Federation, 105229
      • Group of companies "Medci"
    • Moskva, Moskovskaja Oblast, Russian Federation, 119991
      • I.M.Sechenov First Moscow State Medical University (1st MSMU)
  • Sankt Petersburg
    • Pesochny, Sankt Petersburg, Russian Federation, 197758
      • LLC "Oncology scientific centre"
• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Center Ljubljana; Clinical Dept. of Gastroenterology
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron; Servicio de Hepatologia
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofia; Servicio de Hepatologia
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon; Servicio de Aparato Digestivo
  • Madrid, Spain, 28027
    • Clinica Universidad de Navarra Madrid; Servicio de Oncología
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos; Servicio de Oncologia
  • Madrid, Spain, 28050
    • START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Oncologia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet; Servicio Oncologia
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Corporacio Sanitaria Parc Tauli; Servicio de Hepatologia
  • Islas Baleares
    • Palma de Mallorca, Islas Baleares, Spain, 07198
      • Hospital Son Llatzer; Servicio de Oncologia
  • LA Coruña
    • Santiago de Compostela, LA Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
  • Navarra
    • Pamplona/iruña, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra; Servicio de Hepatologia
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Bern Medizin Gastroenterologie
  • Zürich, Switzerland, 8091
    • Universitätsspital Zürich Medizin Gastroenterologie; Klinik für Gastroenterologie und Hepatologie
• Taiwan
  • Tainan, Taiwan, 710
    • Chi-Mei Medical Centre; Hematology & Oncology
  • Zhongzheng Dist., Taiwan, 10048
    • National Taiwan University Hospital; Oncology
• Thailand
  • Bangkok, Thailand, 10330
    • Chulalongkorn Hospital; Medical Oncology
  • Bangkok, Thailand, 10700
    • Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology
• Turkey
  • Adana, Turkey, 01130
    • Adana Ac?badem Hospital Oncology Department
  • Ankara, Turkey, 06520
    • Memorial Ankara Hastanesi
  • Bakirkoy / Istanbul, Turkey, 34147
    • Bakirkoy Dr. Sadi Konuk Egitim ve Arastirma Hastanesi, Tibbi Onkoloji
  • Bursa, Turkey, 16059
    • Uludag Uni Hospital; Oncology
  • Istanbul, Turkey, 34214
    • Medipol Mega Üniversite Hastanesi Göztepe
  • Izmir, Turkey, 35100
    • Ege Uni Medical Faculty Hospital; Oncology Dept
  • Sihhiye/Ankara, Turkey, 06230
    • Hacettepe Uni Medical Faculty Hospital; Oncology Dept
  • Üsküdar, Turkey, 34662
    • Ac?badem Altunizade Hastanesi; Oncology
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital; Hepatobiliary Unit
  • Liverpool, United Kingdom, L7 8YA
    • The Clatterbridge Cancer Centre NHS Foundation Trust
  • London, United Kingdom, NW3 2QS
    • Royal Free Hospital
  • London, United Kingdom, SE5 9RS
    • King College Hospital NHS Foundation Trust
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital; Clinical trials unit
  • Manchester, United Kingdom, M2O 4BX
    • Christie Hospital Nhs Trust; Medical Oncology
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital; Gastroenterology & Liver Unit
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital; Department of Oncology

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients.
• Disease progression following prior atezolizumab plus bevacizumab combination treatment for HCC, for at least 4 consecutive treatment cycles, and 2 subsequent tumor assessments. It is required that at least 1 tumor assessment shows either stable disease (SD), partial response (PR), or complete response (CR).
• At least one measurable (per RECIST v1.1) target lesion that has not been previously treated with local therapy or, if the target lesion is within the field of previous local therapy, has subsequently progressed in accordance with RECIST v1.1.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 within 7 days prior to randomization
• Child-Pugh class A within 7 days prior to randomization
• Adequate hematologic and end-organ function

Exclusion Criteria:

• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
• History of leptomeningeal disease
• History of hepatic encephalopathy, preceding 6 months, unresponsive to therapy within 3 days
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Atezolizumab + Lenvatinib or Sorafenib; Participants will receive atezolizumab plus lenvatinib or sorafenib. Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.	Drug: Atezolizumab; Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator.; Other Names: Tecentriq; Drug: Lenvatinib; Lenvatinib will be administered once daily by mouth each day of every 21-day study treatment cycle. Participants with a baseline body weight of < 60 kg will receive a daily dose of 8 mg. Participants with a baseline body weight of ≥ 60 kg will receive a daily dose of 12 mg.; Drug: Sorafenib; Sorafenib will be administered at a dose of 800 mg per day, i.e. two tablets of 200 mg swallowed by mouth twice daily (equivalent to a total daily dose of 800 mg) each day of every 21-day study treatment cycle.
Active Comparator: Lenvatinib or Sorafenib; Participants will receive lenvatinib or sorafenib. Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.	Drug: Lenvatinib; Lenvatinib will be administered once daily by mouth each day of every 21-day study treatment cycle. Participants with a baseline body weight of < 60 kg will receive a daily dose of 8 mg. Participants with a baseline body weight of ≥ 60 kg will receive a daily dose of 12 mg.; Drug: Sorafenib; Sorafenib will be administered at a dose of 800 mg per day, i.e. two tablets of 200 mg swallowed by mouth twice daily (equivalent to a total daily dose of 800 mg) each day of every 21-day study treatment cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival (OS) is defined as the time from randomization into the study to death from any cause.	Randomization until death from any cause (approximately 42 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Progression free survival (PFS) is defined as the time from randomization into the study to the first occurrence of disease progression or death from any cause (whichever occurs first).	Randomization until the first occurrence of disease progression or death from any cause whichever occurs first (approximately 42 months)
Confirmed Objective Response Rate (ORR)	Confirmed Objective Response Rate (ORR) is defined as the proportion of patients with a best response of either complete or partial response.	Approximately 42 months
Time to Progression (TTP)	Time to Progression (TTP) is defined as the time from randomization to the first occurrence of disease progression.	Randomization until the first occurrence of disease progression (approximately 42 months)
Duration of Response (DOR)	Duration of Response (DOR) is defined as the time from the first occurrence of a documented confirmed objective response to disease progression or death from any cause (whichever occurs first).	Time from the first occurrence of a confirmed documented objective response to disease progression or death from any cause whichever occurs first (approximately 42 months)
Percentage of Participants With Adverse Events		Throughout study duration (approximately 42 months)
Percentage of Participants With Adverse Events for Combination Treatment, Adverse Events Related to Atezolizumab, and TKI-Related Adverse Events		Throughtout study (approximately 42 months)
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab		Throughout study (approximately 42 months)
Serum Concentration of Atezolizumab		At pre-defined intervals from first administration of study drug to approximately 42 months
Time to confirmed deterioration (TTCD)	Time to confirmed deterioration (TTCD), of health-related quality of life (HRQoL), is defined as the time from randomization to first confirmed deterioration (decrease from baseline of ≥ 10 points) maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks (if Cycle 1-6) or 6 weeks (if after Cycle 6) in the following European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30) scales (separately): physical function, role function, and GHS/QoL.	Randomization to first deterioration maintained for two consecutive assessments, or one assessment followed by death from any cause wthin 3 weeks or 6 weeks (approximately 42 months)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2021
• Primary Completion (Estimated): July 9, 2025
• Study Completion (Estimated): July 9, 2025

Study Registration Dates

• First Submitted: February 23, 2021
• First Submitted That Met QC Criteria: February 23, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): June 17, 2024
• Last Update Submitted That Met QC Criteria: June 14, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Sorafenib; Lenvatinib; Atezolizumab
• Other Study ID Numbers: MO42541

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here ( https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No