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

A Randomized, Double-blinded, Placebo-controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

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

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100021
  • Beijing, China, 100039
  • Chongqing, China, 400038
  • Shanghai, China, 200032
  • Shanghai, China, 200003
  • Tianjin, China
  • Anhui
    • Hefei, Anhui, China, 230022
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
    • Guangzhou, Guangdong, China, 510515
  • Hubei
    • Wuhan, Hubei, China, 430030
  • Jiangsu
    • Nanjing, Jiangsu, China, 210003
    • Nanjing, Jiangsu, China, 210009
  • Liaoning
    • Dalian, Liaoning, China, 116011
    • Dalian, Liaoning, China, 116027
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
• Korea, Republic of
  • Daegu, Korea, Republic of, 702-701
  • Seoul, Korea, Republic of, 138-736
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 152-703
• Taiwan
  • Changhua, Taiwan, 500
  • Tainan, Taiwan, 736
  • Taipei, Taiwan, 10016
  • Taipei, Taiwan, 251
  • Taoyuan, Taiwan, 333

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Sorafenib (Nexavar, 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
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。	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
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).	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
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)..	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
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").	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
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.	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
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.	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
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.	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization
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.	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
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.	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
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.	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
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)).	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1
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.	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): March 1, 2007
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: June 26, 2007
• First Submitted That Met QC Criteria: June 26, 2007
• First Posted (Estimate): June 27, 2007

Study Record Updates

• Last Update Posted (Estimate): April 16, 2014
• Last Update Submitted That Met QC Criteria: March 26, 2014
• Last Verified: March 1, 2014

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; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: 11849