Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer

OBJECTIVES:

• Compare the overall survival in patients with unresectable or recurrent hepatocellular carcinoma treated with nolatrexed dihydrochloride vs doxorubicin.
• Compare time to progression, time to treatment failure, and response rates in patients treated with these regimens.
• Compare the probability of survival at 3, 6, 9, and 12 months in patients treated with these regimens.
• Compare the safety and clinical benefit of these regimens in these patients.
• Compare the response rates and survival of patients who have received prior therapy or no prior therapy after treatment with these two regimens.
• Compare the rates of conversion from unresectable to resectable lesions in patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to CLIP score (0-1 vs 2-3) and Karnofsky performance status (60-70% vs 80-100%). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive nolatrexed dihydrochloride IV continuously on days 1-5.
• Arm II: Patients receive doxorubicin IV on day 1. Treatment continues in both arms every 3 weeks in the absence of unacceptable toxicity or disease progression.

Patients are followed every 2 months for survival.

PROJECTED ACCRUAL: Approximately 446 patients (223 per treatment arm) will be accrued for this study within 12 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven or presumptive diagnosis of hepatocellular carcinoma

• Presumptive diagnosis based on rising alpha-fetoprotein (AFP) levels over 2 assessments, CT scan or MRI of liver, spiral CT scan of portal/splenic vein, and biopsy evidence of cirrhosis
• Unresectable or recurrent disease after prior surgical resection or embolization therapy
• Fibrolamellar histology allowed if considered surgically unresectable based on tumor size, extrahepatic involvement, or multiple lobe involvement
• CLIP (Cancer of the Liver Italian Program) score less than 4
• Concurrent assignment to a transplantation list allowed

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,200/mm^3
• Platelet count at least 80,000/mm^3

Hepatic:

• Bilirubin no greater than 3.0 mg/dL (except for known Gilbert's Syndrome)
• AST no greater than 5 times upper limit of normal (ULN)
• PT no greater than 1.5 times ULN

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• No uncontrolled hypertension within the past 3 months
• No unstable angina, symptomatic congestive heart failure, or myocardial infarction within the past 3 months
• No uncontrolled cardiac arrhythmia

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active bacterial infections
• HIV negative
• No AIDS
• No other primary malignancy except carcinoma in situ of the cervix or urinary bladder or non-melanoma skin cancer
• No mental incapacitation or psychiatric illness that would preclude study participation
• No other severe disease that would preclude study participation
• Candidate for placement of a central venous access device

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Prior biologic therapy allowed
• No concurrent biologic therapy

Chemotherapy:

• No prior IV doxorubicin except intraarterial administration in locoregional therapy

Endocrine therapy:

• Prior endocrine therapy allowed
• No concurrent endocrine therapy

Radiotherapy:

• Prior radiotherapy allowed
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• Surgery allowed if previously unresectable lesions become resectable
• Recovered from any prior surgery
• No concurrent liver transplantation

Other:

• No other concurrent investigational or marketed anticancer drugs
• No other concurrent therapy for hepatocellular carcinoma
• No concurrent terfenadine, astemizole, or cisapride that may not be interrupted during nolatrexed dihydrochloride administration