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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00012324
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : June 26, 2013
Information provided by:
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE March 3, 2001
First Posted Date  ICMJE January 27, 2003
Last Update Posted Date June 26, 2013
Study Start Date  ICMJE September 2000
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2007)
Overall survival
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2007)
  • 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
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer
Official Title  ICMJE A Phase III Randomized Controlled Study Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma (HCC) Treated With THYMITAQ to Patients Treated With Doxorubicin
Brief Summary

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.

Detailed Description


  • 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Liver Cancer
Intervention  ICMJE
  • Drug: doxorubicin hydrochloride
  • Drug: nolatrexed dihydrochloride
Study Arms  ICMJE Not Provided
Publications * Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007 Jul 20;25(21):3069-75.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Enrollment  ICMJE Not Provided
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE November 2005
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE


  • 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



  • 18 and over

Performance status:

  • Karnofsky 60-100%

Life expectancy:

  • Not specified


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


  • 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


  • Creatinine no greater than 2.0 mg/dL


  • 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


  • 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


Biologic therapy:

  • Prior biologic therapy allowed
  • No concurrent biologic therapy


  • No prior IV doxorubicin except intraarterial administration in locoregional therapy

Endocrine therapy:

  • Prior endocrine therapy allowed
  • No concurrent endocrine therapy


  • Prior radiotherapy allowed
  • No concurrent radiotherapy


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


  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Puerto Rico,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00012324
Other Study ID Numbers  ICMJE ZARIX-ZX101-301
CDR0000068506 ( Registry Identifier: PDQ (Physician Data Query) )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE Eximias Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Gregory R. Suplick Eximias Pharmaceutical
PRS Account National Cancer Institute (NCI)
Verification Date October 2005

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP