A Phase III Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma (SHARP)

• ClinicalTrials.gov Identifier: NCT00105443
• Recruitment Status: Completed
• First Posted: March 15, 2005
• Results First Posted: September 27, 2010
• Last Update Posted: October 31, 2014
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 14, 2005
• First Posted Date: March 15, 2005
• Results First Submitted Date: December 11, 2009
• Results First Posted Date: September 27, 2010
• Last Update Posted Date: October 31, 2014
• Study Start Date: March 2005
• Actual Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 7, 2010)

• Overall Survival (OS) [ Time Frame: from randomization to death due to any cause until an average 7.2 months later up to the data cut-off date approximately 19 months after start of enrollment ]
  Overall Survival was defined as the time from date of starting treatment to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
• Time to Symptomatic Progression (TTSP) [ Time Frame: from randomization to the first documented symptomatic progression until an average 4.8 months later up to the data cut-off date approximately 19 months after start of enrollment ]
  TTSP was defined as the time from randomization to the first documented symptomatic progression.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: January 17, 2011)

• Time to Progression (TTP) [ Time Frame: from randomization to disease progression based on radiological assessment until an average 2.8 months later up to the data cut-off date approximately 19 months after start of enrollment ]
  TTP was defined as the time from randomization to disease progression (radiological only). Subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation.
• Disease Control (DC) [ Time Frame: time from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment ]
  The DC is defined as the number of subjects with a best response rating of complete response (CR), partial response (PR), or stable disease (SD) that is maintained at least 28 days from the first manifestation of that rating. Definitions: CR = disappearance of all clinical and radiological tumor lesions; PR = at least 30% decrease in sum of the longest diameters of tumor lesions; SD = neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease.
• Patients Reported Outcome (PRO) by Use of the FACT-Hep Questionnaire [ Time Frame: from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment ]
  PRO is a disease-specific measure, developed as symptom-focused approach in HCC and measured by the response rates for the PWB and FWB subscales of the 45-item Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. The FACT-Hep response rate was based on the number of subjects who achieved the 8-point minimally important difference (MID) for this subscale. FACT-Hep total score ranges from 0 to 180, where the highest score represents a maximum achievable quality of life (QoL) value.

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

Descriptive Information

• Brief Title: A Phase III Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
• Official Title: A Phase III Randomized, 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 of or shrinks liver tumors and/or their metastases. Determine the pharmacokinetics (PK) in patients with liver cancer.

Detailed Description

The following abbreviations were used in the Adverse Event section:

• international normalized ratio (inr)
• Common Terminology Criteria for Adverse Events (ctcae)
• Not Otherwise Specified (nos)
• Gastrointestinal (gi)
• Central nervous system (cns)
• Absolute Neutrophil Count (anc)
• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Creatine phosphokinase (cpk)
• Gammaglutamyltransferase (ggt)
• Genitourinary (gu)
• Atrioventricular (av)

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Drug: Sorafenib (Nexavar, BAY43-9006)
  Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment.
• Drug: Placebo
  Sorafenib-matching placebo tablets were orally administered twice daily (bid).

Study Arms

• Experimental: Sorafenib (Nexavar, BAY43-9006)
  Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
  Intervention: Drug: Sorafenib (Nexavar, BAY43-9006)
• Placebo Comparator: Placebo
  Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
  Intervention: Drug: Placebo

Publications *

• Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.
• 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: October 24, 2008): 602
• Original Enrollment: Not Provided
• Actual Study Completion Date: November 2008
• Actual Primary Completion Date: November 2008 (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 histologically or cytologically documented Hepatocellular Carcinoma (HCC)
• 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 RECIST (Response Evaluation Criteria in Solid Tumors) (2) Not previously treated with local therapy
• Patients who have an ECOG (Eastern Cooperative Oncology Group) PS (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
• Renal failure requiring hemo- or peritoneal dialysis
• History of cardiac disease
• Active clinically serious infections
• Known history of human immunodeficiency virus (HIV) infection
• Known central nervous system 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: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Croatia, France, Germany, Greece, Israel, Italy, Mexico, New Zealand, Peru, Poland, Romania, Russian Federation, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT00105443
• Other Study ID Numbers: 100554; 2004-001773-26 ( 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: 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: October 2014