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

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: NCT00003764
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : January 28, 2010
National Cancer Institute (NCI)
Cancer and Leukemia Group B
Southwest Oncology Group
Information provided by:
Eastern Cooperative Oncology Group

Tracking Information
First Submitted Date  ICMJE November 1, 1999
First Posted Date  ICMJE January 27, 2003
Last Update Posted Date January 28, 2010
Study Start Date  ICMJE December 1999
Actual Primary Completion Date November 2005   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE Not Provided
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00003764 on Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
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 Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia
Official Title  ICMJE Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia
Brief 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.

Detailed Description


  • 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Primary Purpose: Treatment
Condition  ICMJE Leukemia
Intervention  ICMJE
  • Drug: cyclophosphamide
  • Drug: fludarabine phosphate
Study Arms  ICMJE Not Provided
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: April¬†9,¬†2007)
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date November 2005   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE


  • 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



  • 18 and over

Performance status:

  • ECOG 0-2

Life expectancy:

  • Not specified


  • See Disease Characteristics


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


  • Creatinine no greater than 2.0 mg/dL
  • Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL


  • 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


Biologic therapy:

  • Not specified


  • No prior cytotoxic chemotherapy

Endocrine therapy:

  • No prior steroid treatment for CLL


  • Not specified


  • Not specified
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,   South Africa,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00003764
Other Study ID Numbers  ICMJE CDR0000066890
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Group Chair, Eastern Cooperative Oncology Group
Study Sponsor  ICMJE Eastern Cooperative Oncology Group
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Cancer and Leukemia Group B
  • Southwest Oncology Group
Investigators  ICMJE
Study Chair: Ian W. Flinn, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Chair: Michael R. Grever, MD Ohio State University Comprehensive Cancer Center
Study Chair: Mohamad A. Hussein, MD The Cleveland Clinic
PRS Account Eastern Cooperative Oncology Group
Verification Date January 2010

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