Clinical trial NCT01774344: Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma
Official title: A Randomized, Double Blind, Placebo Controlled, Multicenter Phase III Study of Regorafenib in Patients With Hepatocellular Carcinoma (HCC) After Sorafenib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Keywords: Regorafenib
BAY73-4506
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2013-01-24
Enrollment: 573
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: The objective of this study was to evaluate efficacy and safety of regorafenib in patients with advanced liver cancer who had progressed after sorafenib treatment. Patients were treated with regorafenib or placebo using a 2:1 randomization scheme.


Eligibility criteria: Inclusion Criteria:

* Histological or cytological confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases criteria in patients with a confirmed diagnosis of cirrhosis
* Barcelona Clinic Liver Cancer stage Category B or C that cannot benefit from treatments of established efficacy with higher priority such as resection, local ablation, chemoembolization or systemic sorafenib.
* Failure to prior treatment with sorafenib (defined as documented radiological progression according to the radiology charter). Randomization needs to be performed within 10 weeks after the last treatment with sorafenib.
* Tolerability of prior treatment with sorafenib defined as not less than 20 days at a minimum daily dose of 400 mg QD within the last 28 days prior to withdrawal.
* Liver function status Child-Pugh Class A. Child Pugh status should be calculated based on clinical findings and laboratory results during the screening period.

Local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed \>/=4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intraarterial chemotherapy, without lipiodol or embolizing agents are not eligible.

* Eastern Cooperative Oncology Group Performance Status of 0 or 1.
* Adequate bone marrow, liver and renal function as assessed by the following laboratory tests conducted within 7 days before randomization.
* Glomerular filtration rate \>/= 30 ml/min/1.73 m\^2 according to the Modification of diet in renal disease study equation.
* At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1), and modified RECIST for HCC. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion.
* Life expectancy of at least 3 months.
* Women of childbearing potential and men must agree to use adequate contraception .

Exclusion Criteria :

* Sorafenib treatment within 2 weeks of randomization.
* Prior systemic treatment for HCC, except sorafenib.
* Permanent discontinuation of prior sorafenib therapy due to sorafenib related toxicity.
* Known history or symptomatic metastatic brain or meningeal tumors (head CT or MRI at screening to confirm the absence of central nervous system \[CNS\] disease if patient has symptoms suggestive or consistent with CNS disease).
* Uncontrolled hypertension (systolic blood pressure \[BP\] \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management).
* Uncontrolled ascites (defined as not easily controlled with diuretic or paracentesis treatment).
* Ongoing infection \> Grade 2 according to NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) v. 4.0. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required.
* Clinically significant bleeding NCI-CTCAE version 4.0 Grade 3 or higher within 30 days before randomization.
* Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication.
* Patients unable to swallow oral medications.
* Interstitial lung disease with ongoing signs and symptoms at the time of screening.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization (Day 1) of the first subject until 419 days later
Secondary outcomes:
measure: Time to Progression (TTP)
timeFrame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks)
measure: Objective Tumor Response Rate (ORR)
timeFrame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
measure: Disease Control Rate (DCR)
timeFrame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
Other outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization (Day 1) of the first subject to end of follow upto 1710 days
Locations:
city: Los Angeles
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Orange
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Gainesville
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: Worcester
country: United States
state: Massachusetts
city: Minneapolis
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Pittsburgh
country: United States
state: Pennsylvania
city: Richmond
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Pilar
country: Argentina
state: Buenos Aires
city: Camperdown
country: Australia
state: New South Wales
city: Liverpool
country: Australia
state: New South Wales
city: Herston
country: Australia
state: Queensland
city: Clayton
country: Australia
state: Victoria
city: Box Hill
country: Australia
city: Linz
country: Austria
state: Oberösterreich
city: Graz
country: Austria
state: Steiermark
city: Wien
country: Austria
city: Bruxelles - Brussel
country: Belgium
city: La Louviere
country: Belgium
city: Salvador
country: Brazil
state: Bahia
city: Sao Paulo
country: Brazil
city: Hefei
country: China
state: Anhui
city: Fuzhou
country: China
state: Fujian
city: Guangzhou
country: China
state: Guangdong
city: Guangzhou
country: China
state: Guangdong
city: Guangzhou
country: China
state: Guangdong
city: Nanning
country: China
state: Guangxi
city: Harbin
country: China
state: Heilongjiang
city: Wuhan
country: China
state: Hubei
city: Changsha
country: China
state: Hunan
city: Nanjing
country: China
state: Jiangsu
city: Suzhou
country: China
state: Jiangsu
city: Dalian
country: China
state: Liaoning
city: Xi'an
country: China
state: Shaanxi
city: Xi'an
country: China
state: Shaanxi
city: Xi'an
country: China
state: Shaanxi
city: Chengdu
country: China
state: Sichuan
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Chongqing
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Tianjin
country: China
city: Hradec Kralove
country: Czechia
city: Olomouc
country: Czechia
city: Praha 2
country: Czechia
city: Angers
country: France
city: Caen
country: France
city: Clichy
country: France
city: Creteil
country: France
city: Dijon
country: France
city: La Tronche
country: France
city: Lille
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Montpellier Cedex
country: France
city: Nice Cedex 3
country: France
city: Paris
country: France
city: Paris
country: France
city: Perpignan
country: France
city: Reims Cedex
country: France
city: Rennes Cedex
country: France
city: Toulouse
country: France
city: Vandoeuvre les Nancy
country: France
city: Villejuif Cedex
country: France
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: München
country: Germany
state: Bayern
city: Frankfurt
country: Germany
state: Hessen
city: Hannover
country: Germany
state: Niedersachsen
city: Aachen
country: Germany
state: Nordrhein-Westfalen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Mainz
country: Germany
state: Rheinland-Pfalz
city: Magdeburg
country: Germany
state: Sachsen-Anhalt
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Kaposvar
country: Hungary
city: Napoli
country: Italy
state: Campania
city: Bologna
country: Italy
state: Emilia-Romagna
city: Modena
country: Italy
state: Emilia-Romagna
city: Roma
country: Italy
state: Lazio
city: Genova
country: Italy
state: Liguria
city: Bergamo
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Novara
country: Italy
state: Piemonte
city: Torino
country: Italy
state: Piemonte
city: Foggia
country: Italy
state: Puglia
city: Cagliari
country: Italy
state: Sardegna
city: Pisa
country: Italy
state: Toscana
city: Padova
country: Italy
state: Veneto
city: Chiba-shi
country: Japan
state: Chiba
city: Kashiwa-shi
country: Japan
state: Chiba
city: Fukuoka-shi
country: Japan
state: Fukuoka
city: Iizuka-shi
country: Japan
state: Fukuoka
city: Yokohama-shi
country: Japan
state: Kanagawa
city: Kumamoto-shi
country: Japan
state: Kumamoto
city: Osaka-shi
country: Japan
state: Osaka
city: Osakasayama-shi
country: Japan
state: Osaka
city: Utsunomiya-shi
country: Japan
state: Tochigi
city: Chiyoda-ku
country: Japan
state: Tokyo
city: Chuo-ku
country: Japan
state: Tokyo
city: Musashino-shi
country: Japan
state: Tokyo
city: Busan
country: Korea, Republic of
state: Busan Gwang''yeogsi
city: Daegu
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Amsterdam
country: Netherlands
city: Leiden
country: Netherlands
city: Barnaul
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Singapore
country: Singapore
city: Oviedo
country: Spain
state: Asturias
city: Alicante
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Zaragoza
country: Spain
city: Bellinzona
country: Switzerland
state: Ticino
city: Bern
country: Switzerland
city: Kaohsiung City
country: Taiwan
state: Kaohsiung
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan
country: Taiwan
city: Birmingham
country: United Kingdom
state: West Midlands
city: Leeds
country: United Kingdom
state: West Yorkshire
city: Bristol
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Finn RS, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Gerolami R, Caparello C, Cabrera R, Chang C, Sun W, LeBerre MA, Baumhauer A, Meinhardt G, Bruix J. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J Hepatol. 2018 Aug;69(2):353-358. doi: 10.1016/j.jhep.2018.04.010. Epub 2018 Apr 26.
citation: Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6.
citation: Teufel M, Seidel H, Kochert K, Meinhardt G, Finn RS, Llovet JM, Bruix J. Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma. Gastroenterology. 2019 May;156(6):1731-1741. doi: 10.1053/j.gastro.2019.01.261. Epub 2019 Feb 6.