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.

Study Overview

• Status: Completed
• Conditions: Liver Cancer
• Intervention / Treatment: Drug: doxorubicin hydrochloride; Drug: nolatrexed dihydrochloride

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface General Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre - General Campus
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• Puerto Rico
  • Santurce, Puerto Rico, 00909
    • Fundacion de Investagacion De Diego
• United States
  • Arizona
    • Tucson, Arizona, United States, 85715
      • Arizona Clinical Research Center, Incorporated
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Beverly Hills, California, United States, 90211
      • Tower Cancer Research Foundation
    • La Jolla, California, United States, 92037
      • Scripps Cancer Center at Scripps Clinic
    • La Mesa, California, United States, 91942
      • David and Donna Long Center for Cancer Treatment at Sharp Grossmont Hospital
    • Long Beach, California, United States, 90822
      • Veterans Affairs Medical Center - Long Beach
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center - Pacific Campus
    • Sylmar, California, United States, 91342
      • Olive View - UCLA Medical Center Foundation
    • Torrance, California, United States, 90505
      • California Hematology/Oncology Medical Group
  • Delaware
    • Newark, Delaware, United States, 19713
      • Helen F. Graham Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center at Georgetown University Medical Center
  • Florida
    • Hudson, Florida, United States, 34667
      • Florida Cancer Institute - Bayonet Point
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Miami, Florida, United States, 33176
      • Oncology-Hematology Group of South Florida, P.A.
    • Ocala, Florida, United States, 34480
      • Ocala Research Institute, Incorporated
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242-1009
      • Holden Comprehensive Cancer Center at University of Iowa
  • Louisiana
    • Lafayette, Louisiana, United States, 70506
      • Louisiana Oncology Associates - Lafayette
    • New Orleans, Louisiana, United States, 70112
      • Stanley S. Scott Cancer Center at Louisiana State University Medical Center - New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Cancer Center
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • Veterans Affairs Medical Center - Albuquerque
  • New York
    • Bronx, New York, United States, 10467
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Ohio
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Taussig Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Cancer Center
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Cancer Centers of the Carolinas - Eastside
  • Texas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Lubbock, Texas, United States, 79410-1894
      • Joe Arrington Cancer Research and Treatment Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Eximias Pharmaceutical
• Investigators: Study Chair: Gregory R. Suplick, Eximias Pharmaceutical

Publications and helpful links

General 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. doi: 10.1200/JCO.2006.08.4046.

Study record dates

Study Major Dates

• Study Start: September 1, 2000
• Study Completion (Actual): November 1, 2005

Study Registration Dates

• First Submitted: March 3, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): June 26, 2013
• Last Update Submitted That Met QC Criteria: June 25, 2013
• Last Verified: October 1, 2005

More Information

Terms related to this study

• Keywords: advanced adult primary liver cancer; recurrent adult primary liver cancer; localized unresectable adult primary liver cancer; adult primary hepatocellular carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Folic Acid Antagonists; Doxorubicin; Liposomal doxorubicin; Nolatrexed
• Other Study ID Numbers: ZARIX-ZX101-301; CDR0000068506 (Registry Identifier: PDQ (Physician Data Query)); AG-337-301