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

UNC Lineberger Comprehensive Cancer Center

Status and phase

Terminated

Phase 1

Conditions

Liver Cancer

Treatments

Drug: sorafenib tosylate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00767468

LCCC 0717

CDR0000615311 (Other Identifier)

BAYER-UNC-LCCC-0717

P30CA016086 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment

6 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of hepatocellular carcinoma (HCC) according to tissue histology* NOTE: *Recurrence of previously resected HCC does not require tissue confirmation if there is clear radiographic recurrence, in the opinion of the investigator
Locally advanced or metastatic disease OR not eligible for surgical resection or immediate liver transplantation
Child-Pugh class B cirrhosis
- Moderate hepatic dysfunction (bilirubin ≤ 3 times upper limit of normal [ULN]) OR severe hepatic dysfunction (bilirubin > 3 times but ≤ 6 times ULN)
No known brain metastasis unless the metastasis has been stable for > 3 months

PATIENT CHARACTERISTICS:

ECOG performance status 0-1
Life expectancy > 12 weeks
Hemoglobin > 9.0 g/dL
ANC > 1,000/mm^3
Platelet count > 45,000/mm^3
ALT and AST < 7 times ULN
INR < 2.0
Creatinine < 1.7 times ULN OR creatinine clearance > 50 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 2 weeks after completion of study treatment
No history of uncontrolled seizures, CNS disorders, or psychiatric disability that, in the opinion of the investigator, is clinically significant, precludes giving informed consent, or interferes with compliance of oral drug intake
No other concurrent active malignancy
No active clinically serious infection > CTCAE grade 2
No known hypersensitivity to sorafenib tosylate or to any of the excipients
No known or suspected allergy to sorafenib tosylate or to any agent given in the course of this study
No NYHA class III or IV congestive heart failure
No unstable angina
No new onset angina (i.e., within the past 3 months)
No myocardial infarction within the past 6 months
No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management
No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months
No pulmonary hemorrhage/bleeding event > CTCAE grade 2 within the past 4 weeks
No other hemorrhage/bleeding event > CTCAE grade 3 within the past 4 weeks
No variceal bleeding within the past 90 days
No known grade 2 or 3 esophageal varices
No evidence or history of bleeding diathesis or coagulopathy
No significant traumatic injury within the past 4 weeks
No serious non-healing wound, ulcer, or bone fracture
No other serious uncontrolled medical condition (e.g., uncontrolled ascites or encephalopathy) that, in the opinion of the investigator, may compromise study participation
No condition that would impair the patient's ability to swallow whole pills
No malabsorption problem
No active drug or alcohol abuse

PRIOR CONCURRENT THERAPY:

No more than one prior therapy including, but not limited to, any of the following:
- Systemic chemotherapy
- Hepatic artery infusion of chemotherapy
- Chemoembolization
- Radioembolization
- Ablation
At least 4 weeks since prior embolization, resection, or ablation
No prior RAF/MEK/ERK-targeting therapy or VEGF-targeting therapy
More than 4 weeks since prior participation in an investigational drug study
More than 4 weeks since prior major surgery or open biopsy
No concurrent chronic anticoagulation other than 1 mg of warfarin per day for central venous catheter patency
No concurrent St. John's wort or rifampin