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

• ClinicalTrials.gov Identifier: NCT00492752
• Recruitment Status: Completed
• First Posted: June 27, 2007
• Results First Posted: January 13, 2011
• Last Update Posted: April 16, 2014
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: June 26, 2007
• First Posted Date: June 27, 2007
• Results First Submitted Date: December 8, 2010
• Results First Posted Date: January 13, 2011
• Last Update Posted Date: April 16, 2014
• Study Start Date: October 2005
• Actual Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 8, 2010)

Overall Survival [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

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.

• Original Primary Outcome Measures (submitted: June 26, 2007): Overall Survival [ Time Frame: Dec.2007 to Apr.2008 ]

Current Secondary Outcome Measures (submitted: March 1, 2011)

• 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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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.

Original Secondary Outcome Measures (submitted: June 26, 2007)

• Time to symptomatic progression, time to progression, disease control rate, Patient report outcomes, overall response rate, overall response duration, time to response, PK profile [ Time Frame: Aug.2007-Nov.2007 ]
• Correlation between the following baseline characteristics and key clinical endpoints (i.e., response, TTP, TTSP, and OS): tumor pERK, phospho VEGF-R2 concentration, plasma proteomics, and gene expression profiling of blood cells and tumor biopsies [ Time Frame: Aug.2007-Nov.2007 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Drug: Sorafenib (Nexavar, BAY43-9006)
  multikinase inhibitor; Sorafenib 400 mg (orally) twice daily
• Drug: Placebo
  Matching placebo (orally) twice daily

Study Arms

• 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.
  Intervention: Drug: Sorafenib (Nexavar, BAY43-9006)
• Placebo Comparator: Placebo
  Placebo tablets matching in appearance were orally administered bid (twice daily).
  Intervention: Drug: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 20, 2009): 226
• Original Enrollment (submitted: June 26, 2007): 271
• Actual Study Completion Date: July 2009
• Actual Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)

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

  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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, Korea, Republic of, Taiwan

Administrative Information

• NCT Number: NCT00492752
• Other Study ID Numbers: 11849
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Not Provided
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: March 2014