A Phase IB Study of Sorafenib for Patient With Locally Advanced or Metastatic Hepatocellular Carcinoma and Child's B Cirrhosis
- To evaluate the pharmacokinetic parameters of sorafenib tosylate in patients with
locally advanced or metastatic hepatocellular carcinoma and Child-Pugh B cirrhosis.
- To correlate the pharmacokinetic parameters of sorfenib tosylate with hepatic retention
and clearance of technetium Tc 99m mebrofenin (MEB) and technetium Tc 99m sestamibi
- To establish a tolerable dose of sorafenib tosylate based on degree of liver
dysfunction (bilirubin ≤ 3 times upper limit of normal [ULN] or bilirubin > 3 times but
≤ 6 times ULN).
- To correlate the pharmacokinetics MEB and MIBI with the dose-limiting toxicity of
- To explore whether increase in bilirubin consists primarily of conjugated or
unconjugated bilirubin in response to sorafenib tosylate.
- To explore whether there is a correlation between increased bilirubin and decreased
clearance of MEB and/or MIBI.
- To explore whether there is a correlation between survival and MRI characteristics
associated with high tumor VEGF levels.
- To assess VEGF levels directly in available biopsy samples using IHC.
- To determine expression levels of hepatic transport proteins (i.e., OATPs, Pgp, or
MRPs) that may correlate with clearance of sorafenib tosylate.
- To explore whether there is a correlation between survival and activation of the
RAF/MEK/ERK pathway at baseline.
- To estimate median overall survival.
OUTLINE: This is a multicenter study. Patients are stratified according to degree of hepatic
dysfunction (moderate [bilirubin ≤ 3 times upper limit of normal (ULN)] vs severe [bilirubin
> 3 times but ≤ 6 times ULN]).
Patients receive oral sorafenib tosylate twice daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.
Patients undergo hepatic scintigraphy with technetium Tc 99m mebrofinin (MEB) and technetium
Tc 99m sestamibi (MIBI) at baseline. Blood and urine samples are collected periodically for
After completion of study therapy, patients are followed at 3-4 weeks and then every 3
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Correlation between hepatic retention and clearance of technetium Tc 99m mebrofenin (MEB) and technetium Tc 99m sestamibi (MIBI) and clearance (and other pharmacokinetic parameters) of sorafenib tosylate
Bert H. O'Neil, MD
UNC Lineberger Comprehensive Cancer Center
United States: Federal Government
|Duke Comprehensive Cancer Center||Durham, North Carolina 27710|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill||Chapel Hill, North Carolina 27599-7570|