Sorafenib in Treating Patients With Locally Advanced or Metastatic Liver Cancer and Cirrhosis

Phase 1

Terminated

• Conditions: Liver Cancer
• Interventions: Drug: sorafenib tosylate

• Registration Number: NCT00767468
• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

Brief Summary

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib in treating patients with locally advanced or metastatic liver cancer and cirrhosis.

Detailed Description

OBJECTIVES:

Primary

* 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 (MIBI).

Secondary

* 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 sorafenib tosylate.

* 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 pharmacokinetic studies.

After completion of study therapy, patients are followed at 3-4 weeks and then every 3 months thereafter.

Study Timeline

• Study Start: 2008-10
• Study First Submitted: 2008-10-04
• Study First Submitted QC: 2008-10-04
• Study First Posted: 2008-10-07
• Primary Completion: 2010-02
• Study Completion: 2010-11
• Status Verified: 2012-05
• Last Update Submitted: 2012-05-22
• Last Update Posted: 2012-05-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bilirubin Normal to 3x Upper Limit of Normal	sorafenib tosylate	-
Bilirubin >3x to 6x Upper Limit of Normal	sorafenib tosylate	-

Primary Outcome Measures

Name	Time	Method
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	4 years

Secondary Outcome Measures

Name	Time	Method
Tolerable dose of sorafenib tosylate	4 years
Correlation between the pharmacokinetics of MEB and MIBI and the dose-limiting toxicity of sorafenib tosylate	4 years
Conjugated or unconjugated bilirubin increase in response to sorafenib tosylate	4 years
Correlation between increased bilirubin and decreased clearance of MEB and/or MIBI	4 years
Correlation between survival and MRI characteristics associated with high tumor VEGF levels	4 years
Correlation between clearance of sorafenib tosylate and expression levels of hepatic transport proteins	4 years
Correlation between survival and activation of the RAF/MEK/ERK pathway at baseline	7 years
Median overall survival	7 years

Trial Locations

Locations (2)

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Duke Comprehensive Cancer Center; 🇺🇸 Durham, North Carolina, United States