Back to resultsA Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Primary Purpose
Carcinoma, Hepatocellular
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Sorafenib (Nexavar, BAY43-9006)
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Carcinoma, Hepatocellular
Eligibility Criteria
Inclusion Criteria:
- Ages eligible for study: 18 years and above, Genders eligible for study: both
- Patients who have a life expectancy of at least 12 weeks
- Patients with advanced Hepatocellular carcinoma (HCC) (unresectable, and/or metastatic) which has been histologically or cytologically documented
Patients must have at least one tumor lesion that meets both of the following criteria
- Accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST)
- Not been previously treated with local therapy
- Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible. Previously treated lesions will not be selected as target lesions. Local therapy must be completed at least 4 weeks prior to the baseline scan
- Patients who have an Eastern Co-operative Oncology Group (ECOG) Performance Status of 0, 1, or 2
Exclusion Criteria:
- Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: "flat tumor"]&T1 [Tumor invades subepithelial connective tissue]). Any cancer curatively treated > 3 years prior to entry is permitted
- History of cardiac disease
- Active clinically serious infections
- Known history of human immunodeficiency virus (HIV) infection
- Known central nervous system (CNS) tumors including metastatic brain disease
- Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Sorafenib (Nexavar, BAY43-9006)
Placebo
Arm Description
Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.
Placebo tablets matching in appearance were orally administered bid (twice daily).
Outcomes
Primary Outcome Measures
Overall Survival
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Secondary Outcome Measures
Time to Symptomatic Progression (TTSP)
Time to Symptomatic Progression (TTSP) was defined as the time from date of randomization to symptomatic progression. Subjects without symptomatic progression at the time of analysis were censored at their last date of tumor evaluation.
Time to Progression (TTP)
Time to progression (TTP) was defined as the time from date of randomization to radiologically documented disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation。
Disease Control
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD: an increase in the sum of tumor lesions sizes) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR: disappearance of tumor lesions) + total number of Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes) + total number of Stable Disease (SD: steady state of disease); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating).
Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3
The FHSI-8 questionnaire was completed at baseline and every 3 weeks during treatment and at the end of treatment visit only for subjects who withdrew for reasons other than symptomatic progression. Patient reported outcome was measured using the FHSI-8 score changes from baseline throughout the study period. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms)..
Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment
The FACT-Hep questionnaire was also completed to assess patient reported outcome. The FACT-Hep assesses hepatobiliary cancer-related quality of life. FACT-Hep total score ranges from 0 to 180 (0=All questions answered "Not at all"; 180=All questions answered "Very much").
Number of Participants With Different Tumor Response
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR: disappearance of tumor lesions), confirmed* Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes), Stable Disease (SD: steady state of disease), or Progressive Disease (PD: an increase in the sum of tumor lesions sizes)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Duration of Response
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last tumor assessment.
Time to Response
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) ) was defined as the time from date of randomization to the earliest date that the response was first documented.
Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment
Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax.
Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment
Cmaxnorm refers to the maximum plasma concentration of Sorafenib corrected for dose and body weight (Cmaxnorm = Cmax/(mg/kg)).
Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment
Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00492752
Brief Title
A Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Official Title
A Randomized, Double-blinded, Placebo-controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
October 2005 (undefined)
Primary Completion Date
March 2007 (Actual)
Study Completion Date
July 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of the study is
Find out if patients receiving Sorafenib will live longer
Find out if Sorafenib has any effect on patient reported outcomes
Find out if Sorafenib prevents the growth or shrinks liver tumors and / or their metastases
Determine the pharmacokinetics (PK) in patients with liver cancer
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Hepatocellular
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
226 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sorafenib (Nexavar, BAY43-9006)
Arm Type
Experimental
Arm Description
Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo tablets matching in appearance were orally administered bid (twice daily).
Intervention Type
Drug
Intervention Name(s)
Sorafenib (Nexavar, BAY43-9006)
Intervention Description
multikinase inhibitor; Sorafenib 400 mg (orally) twice daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo (orally) twice daily
Primary Outcome Measure Information:
Title
Overall Survival
Description
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Secondary Outcome Measure Information:
Title
Time to Symptomatic Progression (TTSP)
Description
Time to Symptomatic Progression (TTSP) was defined as the time from date of randomization to symptomatic progression. Subjects without symptomatic progression at the time of analysis were censored at their last date of tumor evaluation.
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Time to Progression (TTP)
Description
Time to progression (TTP) was defined as the time from date of randomization to radiologically documented disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation。
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Disease Control
Description
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD: an increase in the sum of tumor lesions sizes) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR: disappearance of tumor lesions) + total number of Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes) + total number of Stable Disease (SD: steady state of disease); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating).
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3
Description
The FHSI-8 questionnaire was completed at baseline and every 3 weeks during treatment and at the end of treatment visit only for subjects who withdrew for reasons other than symptomatic progression. Patient reported outcome was measured using the FHSI-8 score changes from baseline throughout the study period. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms)..
Time Frame
Baseline up to Cycle 1 and Cycle 3. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment
Description
The FACT-Hep questionnaire was also completed to assess patient reported outcome. The FACT-Hep assesses hepatobiliary cancer-related quality of life. FACT-Hep total score ranges from 0 to 180 (0=All questions answered "Not at all"; 180=All questions answered "Very much").
Time Frame
Baseline up to Cycle 3 and end of treatment. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Number of Participants With Different Tumor Response
Description
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR: disappearance of tumor lesions), confirmed* Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes), Stable Disease (SD: steady state of disease), or Progressive Disease (PD: an increase in the sum of tumor lesions sizes)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time Frame
From randomization/start of treatment of the first subject until approximately 23 months after randomization when the subjects on placebo were offered the option to crossover to sorafenib treatment
Title
Duration of Response
Description
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last tumor assessment.
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Time to Response
Description
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) ) was defined as the time from date of randomization to the earliest date that the response was first documented.
Time Frame
From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
Title
Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment
Description
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Time Frame
PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
Title
Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment
Description
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Time Frame
PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
Title
Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment
Description
Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax.
Time Frame
PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
Title
Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment
Description
Cmaxnorm refers to the maximum plasma concentration of Sorafenib corrected for dose and body weight (Cmaxnorm = Cmax/(mg/kg)).
Time Frame
PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
Title
Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment
Description
Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax.
Time Frame
PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ages eligible for study: 18 years and above, Genders eligible for study: both
Patients who have a life expectancy of at least 12 weeks
Patients with advanced Hepatocellular carcinoma (HCC) (unresectable, and/or metastatic) which has been histologically or cytologically documented
Patients must have at least one tumor lesion that meets both of the following criteria
Accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST)
Not been previously treated with local therapy
Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible. Previously treated lesions will not be selected as target lesions. Local therapy must be completed at least 4 weeks prior to the baseline scan
Patients who have an Eastern Co-operative Oncology Group (ECOG) Performance Status of 0, 1, or 2
Exclusion Criteria:
Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: "flat tumor"]&T1 [Tumor invades subepithelial connective tissue]). Any cancer curatively treated > 3 years prior to entry is permitted
History of cardiac disease
Active clinically serious infections
Known history of human immunodeficiency virus (HIV) infection
Known central nervous system (CNS) tumors including metastatic brain disease
Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
Hefei
State/Province
Anhui
ZIP/Postal Code
230022
Country
China
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510060
Country
China
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510515
Country
China
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430030
Country
China
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210003
Country
China
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210009
Country
China
City
Dalian
State/Province
Liaoning
ZIP/Postal Code
116011
Country
China
City
Dalian
State/Province
Liaoning
ZIP/Postal Code
116027
Country
China
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310016
Country
China
City
Beijing
ZIP/Postal Code
100021
Country
China
City
Beijing
ZIP/Postal Code
100039
Country
China
City
Chongqing
ZIP/Postal Code
400038
Country
China
City
Shanghai
ZIP/Postal Code
200003
Country
China
City
Shanghai
ZIP/Postal Code
200032
Country
China
City
Tianjin
Country
China
City
Seoul
State/Province
Seoul Teugbyeolsi
ZIP/Postal Code
152-703
Country
Korea, Republic of
City
Daegu
ZIP/Postal Code
702-701
Country
Korea, Republic of
City
Seoul
ZIP/Postal Code
138-736
Country
Korea, Republic of
City
Changhua
ZIP/Postal Code
500
Country
Taiwan
City
Tainan
ZIP/Postal Code
736
Country
Taiwan
City
Taipei
ZIP/Postal Code
10016
Country
Taiwan
City
Taipei
ZIP/Postal Code
251
Country
Taiwan
City
Taoyuan
ZIP/Postal Code
333
Country
Taiwan
12. IPD Sharing Statement
Citations:
PubMed Identifier
19095497
Citation
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.
Results Reference
result
PubMed Identifier
22240282
Citation
Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. doi: 10.1016/j.ejca.2011.12.006. Epub 2012 Jan 10.
Results Reference
result
PubMed Identifier
28687477
Citation
Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol. 2017 Nov;67(5):999-1008. doi: 10.1016/j.jhep.2017.06.026. Epub 2017 Jul 4. Erratum In: J Hepatol. 2018 Oct;69(4):990-991.
Results Reference
derived
Learn more about this trial
A Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
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