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

A Phase III Randomized Controlled Study Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma (HCC) Treated With THYMITAQ to Patients Treated With Doxorubicin

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective for liver cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different chemotherapy regimens in treating patients who have 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