A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC).

• ClinicalTrials.gov Identifier: NCT00855218
• Recruitment Status: Completed
• First Posted: March 4, 2009
• Results First Posted: September 24, 2012
• Last Update Posted: August 18, 2017
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 3, 2009
• First Posted Date: March 4, 2009
• Results First Submitted Date: August 23, 2012
• Results First Posted Date: September 24, 2012
• Last Update Posted Date: August 18, 2017
• Study Start Date: March 2009
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 2, 2014)

Time to Progression (TTP) - Independent Radiological Review (Primary Analysis) [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]

TTP is defined as the time (days) from randomization to radiological confirmed disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation.

• Original Primary Outcome Measures (submitted: March 3, 2009): Time to progression (TTP) [ Time Frame: Time from randomization to radiological disease progression ]

Current Secondary Outcome Measures (submitted: July 2, 2014)

• Overall Survival (OS) [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]
  Overall Survival (OS) was defined as the time (days) from randomization to death due to any cause. Participants still alive at the time of analysis were censored at their last date of last contact.
• Time to Untreatable Progression (TTUP) [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]
  Time to untreatable progression (TTUP) was defined as the time (days) from randomization to untreatable progression. Participants without untreatable progression at the time of analysis were censored at their last date of tumor evaluation.
• Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES) [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]
  Time to vascular invasion/extrahepatic spread (TTVI/ES) was defined as the time (days) from randomization to vascular invasion/extrahepatic spread. Participants without vascular invasion/extrahepatic spread at the time of analysis were censored at their last date of tumor evaluation.
• Tumor Response - Independent Radiological Review [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]
  Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
• Tumor Response - Investigator Assessment [ Time Frame: From randomization of the first participant until 28 months later (cut-off date) ]
  Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Original Secondary Outcome Measures (submitted: March 3, 2009)

• Overall survival [ Time Frame: Time from randomization to death due to any cause. OS of subjects alive at the time of analysis will be censored at their last data of follow-up. ]
• Time to untreatable progression (TTUP) [ Time Frame: Time from randomization to untreatable progression ]
• Time to vascular invasion/extrahepatic spread [ Time Frame: Time from randomization to the radiological evidence of vascular invasion/extrahepatic spread confirmed by CT/MRI scan. ]
• Patient reported outcome (PRO) [ Time Frame: Measured by FACT-Hep and EQ-5D - The total scores of both scales will be calculated, the scores of each domain and each question at each time point and their difference from baseline will be summarized for each treatment group. ]
• Biomarker analysis [ Time Frame: If a sufficient number of optional biomarker samples are obtained, exploratory correlative analysis will be performed. ]
• Descriptive summary tables will be presented on all safety parameters by treatment group [ Time Frame: Time of consent to 30 days post end of study for SAEs ]

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

Descriptive Information

• Brief Title: A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC).
• Official Title: A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC).
• Brief Summary: This study will look at whether our drug (sorafenib) in combination with chemotherapy delivered directly into your tumor using beads (DC Bead) will slow the progression of the disease. The beads used with the chemotherapy will slowly release the chemotherapy reducing the adverse effects that normally occur with chemotherapy.
• Detailed Description: Safety issues will be reported in Adverse Event section. In addition to the secondary outcome measures, Biomarkers and Patient Report Outcome will also be analyzed as other variables.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Drug: Sorafenib (Nexavar, BAY43-9006)
  800 mg sorafenib (4 tablets) will be taken daily (400mg b.i.d. [twice daily], 2 tablets). Transarterial Chemoembolization (TACE) using DC Bead
• Drug: Placebo
  4 tablets of placebo will be taken daily (2 tablets b.i.d). TACE using DC Bead

Study Arms

• Experimental: Sorafenib (Nexavar, BAY43-9006) + TACE
  Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Patients were then also treated with Transarterial Chemoembolization (TACE) performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of sorafenib, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.)
  Intervention: Drug: Sorafenib (Nexavar, BAY43-9006)
• Placebo Comparator: Placebo + TACE
  Placebo was to be orally administered as 2 tablets bid (twice daily). Patients were then also treated with TACE performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of placebo, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.)
  Intervention: Drug: Placebo

• Publications *: Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, Paik SW, Reig M, Kim DY, Chau GY, Luca A, Del Arbol LR, Leberre MA, Niu W, Nicholson K, Meinhardt G, Bruix J. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. J Hepatol. 2016 May;64(5):1090-1098. doi: 10.1016/j.jhep.2016.01.012. Epub 2016 Jan 22.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 28, 2010): 307
• Original Estimated Enrollment (submitted: March 3, 2009): 350
• Actual Study Completion Date: February 2013
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Unresectable, multinodular asymptomatic tumor without vascular invasion or extrahepatic spread
• Confirmed Diagnosis of HCC:
• Cirrhotic subjects: Clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria
• HCC can be defined in cirrhotic subjects by one imaging technique (Computed tomography [CT] scan, Magnetic resonance imaging [MRI], or second generation contrast ultrasound) showing a nodule larger than 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1-2 cm in diameter.
• Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria.
• Non-cirrhotic subjects:

For subjects without cirrhosis, histological or cytological confirmation is mandatory

• Documentation of original biopsy for diagnosis is acceptable
• Child Pugh class A without ascites
• Adequate bone marrow, liver and renal function as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to randomization:

Exclusion Criteria:

• Patients on a liver transplantation list or with advanced liver disease as defined below:
• Child Pugh B and C
• Active gastrointestinal bleeding
• Encephalopathy
• Ascites
• Lesions having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation can not be selected as the target lesions.

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: Australia, Austria, Belgium, Canada, China, France, Germany, Italy, Korea, Republic of, Singapore, Spain, Taiwan, United States

Administrative Information

• NCT Number: NCT00855218
• Other Study ID Numbers: 12918; 2008-005056-24 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Therapeutic Area Head, Bayer Schering Pharma AG
• 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: July 2017