Clinical trial NCT00012324: Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Cancer
Keywords: localized unresectable adult primary liver cancer
advanced adult primary liver cancer
recurrent adult primary liver cancer
adult primary hepatocellular carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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: 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.

Eligibility 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

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

Primary outcomes:
measure: Overall survival
Secondary outcomes:
measure: Time to progression
measure: Time to treatment failure
measure: Response rate (complete response, partial response, stable disease)
measure: Survival probabilities at 3, 6, 9, and 12 months
measure: Safety
measure: Response to treatment in patients with and without prior therapy
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Clinical Research Center, Incorporated
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: La Jolla
country: United States
facility: Scripps Cancer Center at Scripps Clinic
state: California
city: La Mesa
country: United States
facility: David and Donna Long Center for Cancer Treatment at Sharp Grossmont Hospital
state: California
city: Long Beach
country: United States
facility: Veterans Affairs Medical Center - Long Beach
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center - Pacific Campus
state: California
city: Sylmar
country: United States
facility: Olive View - UCLA Medical Center Foundation
state: California
city: Torrance
country: United States
facility: California Hematology/Oncology Medical Group
state: California
city: Newark
country: United States
facility: Helen F. Graham Cancer Center
state: Delaware
city: Washington
country: United States
facility: Lombardi Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Hudson
country: United States
facility: Florida Cancer Institute - Bayonet Point
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Miami
country: United States
facility: Oncology-Hematology Group of South Florida, P.A.
state: Florida
city: Ocala
country: United States
facility: Ocala Research Institute, Incorporated
state: Florida
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Cancer Center
state: Illinois
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Lafayette
country: United States
facility: Louisiana Oncology Associates - Lafayette
state: Louisiana
city: New Orleans
country: United States
facility: Stanley S. Scott Cancer Center at Louisiana State University Medical Center - New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: Veterans Affairs Medical Center - Albuquerque
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein Cancer Center at Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: New York Weill Cornell Cancer Center at Cornell University
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Albert Einstein Cancer Center
state: Pennsylvania
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas - Eastside
state: South Carolina
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Santurce
country: Puerto Rico
facility: Fundacion de Investagacion De Diego
Study officials:
affiliation: Eximias Pharmaceutical
name: Gregory R. Suplick
role: STUDY_CHAIR
References:
citation: 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.