Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	18 and over	Pharmaceutical / Industry	ZARIX-ZX101-301 AG-337-301, NCT00012324

Objectives

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

Entry Criteria

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

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

Patient Characteristics:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,200/mm³
• Platelet count at least 80,000/mm³

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

Expected Enrollment

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

Outcomes

Overall survival

Time to progression
Time to treatment failure
Response rate (complete response, partial response, stable disease)
Survival probabilities at 3, 6, 9, and 12 months
Safety
Response to treatment in patients with and without prior therapy

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.

Gish RG, Porta C, Lazar L, et al.: Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 25 (21): 3069-75, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Eximias Pharmaceutical Corporation

Gregory Suplick, Protocol chair		Ph: 610-560-0637

Registry Information
Official Title		A Phase III Randomized Controlled Study Comparing the Survival of Patients with Unresectable Hepatocellular Carcinoma (HCC) Treated with THYMITAQ to Patients Treated with Doxorubicin
Trial Start Date		2000-09-25
Registered in ClinicalTrials.gov		NCT00012324
Date Submitted to PDQ		2001-01-29
Information Last Verified		2005-10-06

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