Epirubicin and Celecoxib in Treating Patients With Hepatocellular Carcinoma

OBJECTIVES:

• Determine the maximum tolerated dose of epirubicin when administered with celecoxib in patients with hepatocellular carcinoma.
• Determine the response rate in patients treated with this regimen.
• Determine the 6-month and overall survival of patients treated with this regimen.
• Determine the toxicity profile of this regimen in these patients.
• Determine the effects of this regimen on serum levels of vascular endothelial growth factor and correlate these effects with response in these patients.
• Correlate the expression of cyclooxygenase-2 in tumor tissue and nonmalignant liver tissue with response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of epirubicin.

• Phase I:Patients receive epirubicin IV over 20 minutes on day 1 and oral celecoxib twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-5 patients receive escalating doses of epirubicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 3 of 5 patients experience dose-limiting toxicity.

• Phase II: Additional patients are accrued and treated as in phase I at the MTD of epirubicin.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-52 patients (3-15 for phase I and 12-37 for phase II) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of localized or metastatic hepatocellular carcinoma (HCC) by 1 of the following:

• Biopsy
• Alpha-fetoprotein (AFP) measurement (greater than 400 ng/mL if hepatitis B surface antigen [HBsAg] is negative OR greater than 1,000 ng/mL if HBsAg is positive)
• Not amenable to surgical resection or liver-directed therapy
• Measurable or evaluable disease* NOTE: *Changes in AFP alone are not sufficient
• Child-Pugh score A or B

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 75,000/mm^3

Hepatic

• Bilirubin no greater than 3.0 mg/dL
• AST no greater than 5 times upper limit of normal

Renal

• Creatinine no greater than 2.0 mg/dL

Cardiovascular

• LVEF greater than 45% by MUGA or echocardiogram

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No requirement for nonsteroidal anti-inflammatory drugs (NSAIDs) except low-dose (81 mg) aspirin
• No known hypersensitivity to aspirin or other NSAIDs
• No contraindication to cyclooxygenase-2 (COX-2) inhibitor therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior therapy for HCC