A Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma - Full Text View

Sponsor:	Bayer
Information provided by:	Bayer
ClinicalTrials.gov Identifier:	NCT00492752

Purpose

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

Condition	Intervention	Phase
Carcinoma, Hepatocellular	Drug: Nexavar (Sorafenib, BAY43-9006) Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Randomized, Double-blinded, Placebo-controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Liver Cancer

Drug Information available for: Sorafenib Sorafenib tosylate

U.S. FDA Resources

Further study details as provided by Bayer:

Primary Outcome Measures:

Overall Survival [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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 [ 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 ] [ Designated as safety issue: No ]
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.

Enrollment:	226
Study Start Date:	October 2005
Study Completion Date:	July 2009
Primary Completion Date:	March 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Sorafenib (Nexavar, BAY43-9006) 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.	Drug: Nexavar (Sorafenib, BAY43-9006) multikinase inhibitor; Sorafenib 400 mg (orally) twice daily
Placebo Comparator: Placebo Placebo tablets matching in appearance were orally administered bid (twice daily).	Drug: Placebo Matching placebo (orally) twice daily

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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
1. Accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST)
2. 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00492752

Locations

China, Anhuii

Hefei, Anhuii, China, 230022
China, Guangdong

Guangzhou, Guangdong, China, 510515

Guangzhou, Guangdong, China, 510060
China, Hubei

Wuhan, Hubei, China, 430030
China, Jiangsu

Nanjing, Jiangsu, China, 210009

Nanjing, Jiangsu, China, 210002
China, Liaoning

Dalian, Liaoning, China, 116027

Dalian, Liaoning, China, 116011
China, Zhejiang

Hangzhou, Zhejiang, China, 310016
China

Beijing, China, 100039

Beijing, China, 100021

Chongqing, China, 400038

Shanghai, China, 200032

Shanghai, China, 200003

Tianjin, China
Korea, Republic of

Daegu, Korea, Republic of, 702-701

Seoul, Korea, Republic of, 138-736

Seoul, Korea, Republic of, 152-703
Taiwan

Changhua, Taiwan, 500

Tainan, Taiwan, 736

Taipei, Taiwan, 100

Taipei, Taiwan, 112

Taoyuan, Taiwan, 333

Sponsors and Collaborators

Bayer

Investigators

Study Director:

Bayer Study Director

Bayer

More Information

Additional Information:

Click here and search for drug information provided by the FDA. This link exits the ClinicalTrials.gov site

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No publications provided by Bayer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Epub 2008 Dec 16.

Responsible Party:	Therapeutic Area Head, Bayer HealthCare AG
ClinicalTrials.gov Identifier:	NCT00492752 History of Changes
Other Study ID Numbers:	11849
Study First Received:	June 26, 2007
Results First Received:	December 8, 2010
Last Updated:	March 1, 2011
Health Authority:	Taiwan: National Bureau of Controlled Drugs; China: State Food and Drug Administration; South Korea: Korea Food and Drug Administration (KFDA)

Additional relevant MeSH terms:

Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site

Digestive System Diseases
Liver Diseases
Sorafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 12, 2012