Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia

Leukemia Clinical Trial

Official title:

Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00003764
• Other study ID #: CDR0000066890
• Secondary ID: E2997CALGB-10103
• Status: Completed
• Phase: Phase 3
• Start date: March 9, 2000

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known whether combining cyclophosphamide with fludarabine is more effective than fludarabine alone in treating chronic lymphocytic leukemia.

PURPOSE: Randomized phase III trial to study the effectiveness of fludarabine with or without cyclophosphamide in treating patients who have chronic lymphocytic leukemia that has not been treated previously.

Description:

OBJECTIVES:

• Compare the efficacy of fludarabine with or without cyclophosphamide in terms of complete remission rate and overall survival in patients with previously untreated B cell chronic lymphocytic leukemia (CLL).

• Compare the toxicities of these 2 regimens in this patient population.

• Determine whether the expression of proteins specifically implicated in the regulation of DNA damage induced apoptosis of lymphoid cells (i.e., p53; mdm2; GST; Bcl-2; Mcl-1; Bax; p27; and caspase-3) correlates with response to chemotherapy in these patients.

• Determine whether there is a relationship between clinical response or resistance and differential expression of genes in the CLL cells either at initiation of therapy or following relapse and progression.

• Correlate mutations in immunoglobulin heavy chain variable region genes with clinical response or resistance in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (O-II vs III-IV). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5.

• Arm II: Patients receive fludarabine as in arm I plus cyclophosphamide IV over 1 hour on day 1.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months until disease progression.

PROJECTED ACCRUAL: A total of 280 patients will be accrued for this study over 2 to 2.5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 280
• Est. primary completion date: November 2005
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia (CLL) of any stage as defined by the following:

• Peripheral blood absolute lymphocyte count greater than 5,000/mm^3 within 14 days prior to study

• Lymphocytes must be small to moderate size with no more than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically

• Phenotypically characterized as B-CLL

• Must have one of the following characteristics indicating need for chemotherapy:

• Progressive marrow failure (hemoglobin less than 10 g/dL and/or platelet count less than 100,000/mm^3)

• Progressive lymphocytosis with an increase of more than 50% over a 2 month period or anticipated doubling time of less than 6 months

• Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly

• Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy

• At least 10% weight loss within 6 months of study

• Extreme fatigue

• Fevers greater than 100.5 degrees F for 2 weeks without evidence of infection

• Night sweats without evidence of infection

• No autoimmune anemia or autoimmune thrombocytopenia

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 mg/dL unless secondary to tumor

Renal:

• Creatinine no greater than 2.0 mg/dL

• Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL

Other:

• No other prior or concurrent malignancy within the past 2 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix

• No active infection requiring oral or intravenous antibiotics

• Not pregnant or nursing

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior cytotoxic chemotherapy

Endocrine therapy:

• No prior steroid treatment for CLL

Radiotherapy:

• Not specified

Surgery:

• Not specified

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• cyclophosphamide

• fludarabine phosphate

Locations

Country	Name	City	State
Canada	McGill University	Montreal	Quebec
Puerto Rico	University of Puerto Rico School of Medicine Medical Sciences Campus	San Juan
South Africa	Pretoria Academic Hospital	Pretoria
United States	Veterans Affairs Medical Center - Albany	Albany	New York
United States	MBCCOP - University of New Mexico HSC	Albuquerque	New Mexico
United States	Veterans Affairs Medical Center - Albuquerque	Albuquerque	New Mexico
United States	Harrington Cancer Center	Amarillo	Texas
United States	Veterans Affairs Medical Center - Amarillo	Amarillo	Texas
United States	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Veterans Affairs Medical Center - Ann Arbor	Ann Arbor	Michigan
United States	Northeast Alabama Regional Medical Center	Anniston	Alabama
United States	Veterans Affairs Medical Center - Asheville	Asheville	North Carolina
United States	CCOP - Atlanta Regional	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Medical Center of Aurora - South Campus	Aurora	Colorado
United States	University of Colorado Cancer Center at University of Colorado Health Sciences Center	Aurora	Colorado
United States	Marlene and Stewart Greenebaum Cancer Center, University of Maryland	Baltimore	Maryland
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Veterans Affairs Medical Center - Baltimore	Baltimore	Maryland
United States	Green Mountain Oncology Group	Bennington	Vermont
United States	Hematology Oncology Associates of the Quad Cities	Bettendorf	Iowa
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Veterans Affairs Medical Center - Biloxi	Biloxi	Mississippi
United States	University of Alabama at Birmingham Comprehensive Cancer Center	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Cancer Research Center at Boston Medical Center	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Tufts - New England Medical Center	Boston	Massachusetts
United States	Boulder Community Hospital	Boulder	Colorado
United States	Albert Einstein Clinical Cancer Center	Bronx	New York
United States	Veterans Affairs Medical Center - Buffalo	Buffalo	New York
United States	Vermont Cancer Center at University of Vermont	Burlington	Vermont
United States	Cooper University Hospital	Camden	New Jersey
United States	CCOP - Cedar Rapids Oncology Project	Cedar Rapids	Iowa
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	Veterans Affairs Medical Center - Charleston	Charleston	South Carolina
United States	Martha Jefferson Hospital	Charlottesville	Virginia
United States	Louis A. Weiss Memorial Hospital	Chicago	Illinois
United States	MBCCOP - University of Illinois at Chicago	Chicago	Illinois
United States	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Veterans Affairs Medical Center - Chicago (Westside Hospital)	Chicago	Illinois
United States	Veterans Affairs Medical Center - Lakeside Chicago	Chicago	Illinois
United States	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio
United States	Veterans Affairs Medical Center - Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Penrose Cancer Center	Colorado Springs	Colorado
United States	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri
United States	Veterans Affairs Medical Center - Columbia (Truman Memorial)	Columbia	Missouri
United States	Arthur G. James Cancer Hospital - Ohio State University	Columbus	Ohio
United States	CCOP - Columbus	Columbus	Ohio
United States	NorthEast Oncology Associates	Concord	North Carolina
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Veterans Affairs Medical Center - Dallas	Dallas	Texas
United States	CCOP - Geisinger Clinic and Medical Center	Danville	Pennsylvania
United States	Genesis Medical Center	Davenport	Iowa
United States	CCOP - Dayton	Dayton	Ohio
United States	Veterans Affairs Medical Center - Dayton	Dayton	Ohio
United States	CCOP - Central Illinois	Decatur	Illinois
United States	Veterans Affairs Medical Center - Atlanta (Decatur)	Decatur	Georgia
United States	CCOP - Colorado Cancer Research Program, Incorporated	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian-St Luke's Medical Center	Denver	Colorado
United States	Rocky Mountain Cancer Centers - Rose	Denver	Colorado
United States	St. Joseph Hospital	Denver	Colorado
United States	CCOP - Iowa Oncology Research Association	Des Moines	Iowa
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	Veterans Affairs Medical Center - Detroit	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Veterans Affairs Medical Center - Durham	Durham	North Carolina
United States	Veterans Affairs Medical Center - East Orange	East Orange	New Jersey
United States	Elmhurst Hospital Center	Elmhurst	New York
United States	Swedish Medical Center	Englewood	Colorado
United States	CCOP - Evanston	Evanston	Illinois
United States	CCOP - Merit Care Hospital	Fargo	North Dakota
United States	Veterans Affairs Medical Center - Fargo	Fargo	North Dakota
United States	Cape Fear Valley Health System	Fayetteville	North Carolina
United States	Broward General Medical Center	Fort Lauderdale	Florida
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	Fort Wayne Medical Oncology and Hematology, Incorporated	Fort Wayne	Indiana
United States	University of Texas Medical Branch	Galveston	Texas
United States	CCOP - Grand Rapids	Grand Rapids	Michigan
United States	CCOP - St. Vincent Hospital Cancer Center, Green Bay	Green Bay	Wisconsin
United States	CCOP - Greenville	Greenville	South Carolina
United States	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Veterans Affairs Medical Center - Hines (Hines Junior VA Hospital)	Hines	Illinois
United States	Memorial Regional Hospital Comprehensive Cancer Center	Hollywood	Florida
United States	MBCCOP - Hawaii	Honolulu	Hawaii
United States	University of Texas - MD Anderson Cancer Center	Houston	Texas
United States	Veterans Affairs Medical Center - Houston	Houston	Texas
United States	St. Mary's Medical Center	Huntington	West Virginia
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Veterans Affairs Medical Center - Jackson	Jackson	Mississippi
United States	Queens Cancer Center of Queens Hospital	Jamaica	New York
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	CCOP - Kansas City	Kansas City	Missouri
United States	Kansas Cancer Institute at the University of Kansas Medical Center	Kansas City	Kansas
United States	Veterans Affairs Medical Center - Kansas City	Kansas City	Missouri
United States	Lenoir Memorial Hospital Cancer Center	Kinston	North Carolina
United States	Rebecca and John Moores UCSD Cancer Center	La Jolla	California
United States	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Veterans Affairs Medical Center - Las Vegas	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth Medical School	Lebanon	New Hampshire
United States	Markey Cancer Center at University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Veterans Affairs Medical Center - Lexington	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Veterans Affairs Medical Center - Little Rock (McClellan)	Little Rock	Arkansas
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center	Los Angeles	California
United States	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California
United States	Baptist Hospital East - Louisville	Louisville	Kentucky
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	North Shore University Hospital	Manhasset	New York
United States	CCOP - Marshfield Clinic Research Foundation	Marshfield	Wisconsin
United States	Veterans Affairs Outpatient Clinic - Martinez	Martinez	California
United States	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois
United States	Danville Radiation Therapy Center	Memphis	Tennessee
United States	University of Tennessee Cancer Institute	Memphis	Tennessee
United States	CCOP - Mount Sinai Medical Center	Miami Beach	Florida
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Veterans Affairs Medical Center - Minneapolis	Minneapolis	Minnesota
United States	MBCCOP - Gulf Coast	Mobile	Alabama
United States	Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	CCOP - Ochsner	New Orleans	Louisiana
United States	MBCCOP - LSU Health Sciences Center	New Orleans	Louisiana
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Veterans Affairs Medical Center - New Orleans	New Orleans	Louisiana
United States	Herbert Irving Comprehensive Cancer Center at Columbia University	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center, NY	New York	New York
United States	New York Weill Cornell Cancer Center at Cornell University	New York	New York
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	Virginia Oncology Associates - Norfolk	Norfolk	Virginia
United States	CCOP - Bay Area Tumor Institute	Oakland	California
United States	Oklahoma University Medical Center at University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Veterans Affairs Medical Center - Oklahoma City	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Chao Family Comprehensive Cancer Center at University of California Irvine Cancer Center	Orange	California
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	CCOP - Western Regional, Arizona	Phoenix	Arizona
United States	Veterans Affairs Medical Center - Phoenix (Carl T. Hayden)	Phoenix	Arizona
United States	FirstHealth Moore Regional Hospital	Pinehurst	North Carolina
United States	Hillman Cancer Center at University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	CCOP - Columbia River Oncology Program	Portland	Oregon
United States	Veterans Affairs Medical Center - Portland	Portland	Oregon
United States	Lifespan: The Miriam Hospital	Providence	Rhode Island
United States	St. Mary-Corwin Regional Medical Center	Pueblo	Colorado
United States	Ministry Medical Group - Northern Region	Rhinelander	Wisconsin
United States	MBCCOP - Massey Cancer Center	Richmond	Virginia
United States	West Suburban Center for Cancer Care	River Forest	Illinois
United States	Oncology and Hematology Associates of Southwest Virginia, Inc.	Roanoke	Virginia
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Saint Anthony Medical Center	Rockford	Illinois
United States	CCOP - Beaumont	Royal Oak	Michigan
United States	University of California Davis Cancer Center	Sacramento	California
United States	Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph	Saint Joseph	Michigan
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri
United States	Missouri Baptist Cancer Center	Saint Louis	Missouri
United States	St. Louis University Hospital Cancer Center	Saint Louis	Missouri
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Veterans Affairs Medical Center - Salt Lake City	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Veterans Affairs Medical Center - San Antonio (Murphy)	San Antonio	Texas
United States	Veterans Affairs Medical Center - San Diego	San Diego	California
United States	Veterans Affairs Medical Center - San Francisco	San Francisco	California
United States	CCOP - Santa Rosa Memorial Hospital	Santa Rosa	California
United States	CCOP - Virginia Mason Research Center	Seattle	Washington
United States	Puget Sound Oncology Consortium	Seattle	Washington
United States	Veterans Affairs Medical Center - Seattle	Seattle	Washington
United States	Louisiana State University Health Sciences Center - Shreveport	Shreveport	Louisiana
United States	Veterans Affairs Medical Center - Shreveport	Shreveport	Louisiana
United States	CCOP - Sioux Community Cancer Consortium	Sioux Falls	South Dakota
United States	CCOP - Northern Indiana CR Consortium	South Bend	Indiana
United States	Providence Cancer Institute at Providence Hospital	Southfield	Michigan
United States	CCOP - Upstate Carolina	Spartanburg	South Carolina
United States	CCOP - Cancer Research for the Ozarks	Springfield	Missouri
United States	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	Syracuse	New York
United States	University Hospital at State University of New York - Upstate Medical University	Syracuse	New York
United States	Veterans Affairs Medical Center - Syracuse	Syracuse	New York
United States	CCOP - Northwest	Tacoma	Washington
United States	Madigan Army Medical Center	Tacoma	Washington
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	CCOP - Scott and White Hospital	Temple	Texas
United States	Veterans Affairs Medical Center - Temple	Temple	Texas
United States	Rocky Mountain Cancer Centers	Thornton	Colorado
United States	David Grant Medical Center	Travis Air Force Base	California
United States	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona
United States	Veterans Affairs Medical Center - Tucson	Tucson	Arizona
United States	CCOP - Carle Cancer Center	Urbana	Illinois
United States	Lombardi Cancer Center at Georgetown University Medical Center	Washington	District of Columbia
United States	MBCCOP - Howard University Cancer Center	Washington	District of Columbia
United States	Veterans Affairs Medical Center - Washington, DC	Washington	District of Columbia
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	Palm Beach Cancer Institute	West Palm Beach	Florida
United States	Veterans Affairs Medical Center - White River Junction	White River Junction	Vermont
United States	CCOP - Wichita	Wichita	Kansas
United States	Veterans Affairs Medical Center - Wichita	Wichita	Kansas
United States	New Hanover Regional Medical Center	Wilmington	North Carolina
United States	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina
United States	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center - University Campus	Worcester	Massachusetts
United States	CCOP - MainLine Health	Wynnewood	Pennsylvania

Sponsors (4)

Lead Sponsor	Collaborator
Eastern Cooperative Oncology Group	Cancer and Leukemia Group B, National Cancer Institute (NCI), SWOG Cancer Research Network

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico,  South Africa, 

References & Publications (6)

Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, Lampson B, Larson RA, Caligiuri MA, Heerema NA. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphoc — View Citation

Dewald GW, Paietta E, Goloubeva O, et al.: Correlation of interphase fluorescence in situ hybridization (FISH) anomalies with cell morphology and immunophenotyping in chronic lymphocytic leukemia (B-CLL). [Abstract] Blood 100 (11 pt 1): A-2334, 2002.

Flinn IW, Kumm E, Grever MR, et al.: Fludarabine and cyclophosphamide produces a higher complete response rate and more durable remissions than fludarabine in patients with previously untreated CLL: Intergroup trial E2997. [Abstract] Blood 104 (11): A-475

Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic — View Citation

Grever MR, Lucas DM, Dewald GW, et al.: Outcome of treatment with fludarabine versus fludarabine and cyclophosphamide in chronic lymphocytic leukemia (CLL) is adversely impacted by high risk genetic features: results from ECOG 2997. [Abstract] Blood 104 (

Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, Flinn IW, Tallman MS, Appelbaum FR, Larson RA, Paietta E, Jelinek DF, Gribben JG, Byrd JC. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chroni — View Citation