Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	Not specified	Other	LRF-CLL4 LRG-MRC-LEUK-CLL4, EU-99030, MRC-LEUK-CLL4, NCT00004218, EUDRACT-58585610, ISRCTN58585610

Objectives

1. Compare the survival rate of patients with newly diagnosed chronic lymphocytic leukemia treated with chlorambucil alone vs fludarabine with or without cyclophosphamide.
2. Compare the response rate and duration of remission in patients treated with these regimens.
3. Compare the toxic effects of these regimens in these patients.
4. Compare the quality of life of patients treated with these regimens.
5. Determine the impact of the drug response information provided by the DiSC assay on response rate and survival in relapsed or nonresponding patients.
6. Assess the prognostic value of five genetic markers: trisomy 12 and deletions at 11q23, 13q14, p53, and 6q21 in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) requiring therapy and meeting the following criteria:
  • Previously untreated disease
  • Peripheral blood morphology, excluding other leukemia and low-grade lymphoma in leukemic phase
  • Cell markers: CD5+, CD23+, SmIg (weak), CD79b-, FMC7-
  • Persistent lymphocytosis (greater than 10,000/mm³)
  • At least 40% bone marrow infiltration



• Stage 0 or I progressive disease indicated by at least one of the following:
  • Persistent rise in lymphocyte count with doubling time less than 12 months
  • Downward trend in hemoglobin and/or platelet count
  • At least 50% increase in size of liver and/or spleen and/or lymph nodes
  • Appearance of lymphadenopathy, hepatomegaly, or splenomegaly
  • Constitutional symptoms caused by disease
    • Pyrexia
    • Night sweats
    • Weight loss

  OR




• Stage II or III

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No concurrent corticosteroids (e.g., dexamethasone) as antiemetics

Radiotherapy

• Not specified

Surgery

• Not specified

Patient Characteristics:

Age:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)*
• SGOT/SGPT no greater than 2 times ULN*

 [Note: * Unless due to CLL]

Renal:

• Creatinine clearance at least 30 mL/min

Other:

• No other cancer or life-threatening disease
• Not pregnant
• Fertile patients must use effective contraception during and for 6 months after study therapy

Expected Enrollment

A total of 750 patients will be accrued for this study within 6-7 years.

Outline

This is a randomized study. Patients enter one of three treatment arms in the first randomization. Depending on response, some patients may also participate in a second randomization to one of two treatment arms.

• First randomization:
  • Arm I: Patients receive oral chlorambucil daily for 7 days. Treatment repeats every 4 weeks until maximum response or up to 1 year.
  
  
  
  • Arm II: Patients receive fludarabine IV or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.
  
  
  
  • Arm III: Patients receive cyclophosphamide IV and fludarabine IV for 3 days or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.
  
  
  

  Patients who relapse after being in remission for at least 1 year may repeat the initial therapy or may participate in a second randomization. Patients who experience progressive disease or relapse within 1 year after treatment proceed to a second randomization.

• Second randomization:
  • Arm I: Treatment is guided by the results of the DiSC assay. Treatment may be one of the first-line treatments with fludarabine or standard CHOP chemotherapy repeated every 4 weeks (cyclophosphamide IV, doxorubicin IV, vincristine IV, and oral prednisolone on days 1-5) or any other therapy guided by the results of the DiSC assay.
  
  
  
  • Arm II: Treatment is physician's choice, which may include any of the options in arm I.
  
  
  

Quality of life is assessed prior to initial therapy; at 3, 6, and 12 months; and then annually thereafter.

Patients are followed annually for survival.

Else M, Smith AG, Cocks K, et al.: Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol 143 (5): 690-7, 2008.[PUBMED Abstract]

Catovsky D, Richards S, Matutes E, et al.: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370 (9583): 230-9, 2007.[PUBMED Abstract]

Dearden CE, Wade RL, Else M, et al.: The combination of fludarabine and cyclophosphamide has a beneficial effect on the incidence of hemolytic anemia in chronic lymphocytic leukemia: results from the UK LRF CLL4 trial. [Abstract] Blood 110 (11): A-2044, 2007.

Trial Contact Information

Trial Lead Organizations

Leukemia Research Fund

Daniel Catovsky, MD, Protocol chair		Ph: 44-20-7808-2880 ext.2875 Email: daniel.catovsky@icr.ac.uk

Medical Research Council's Working Party on Leukemia in Adults and Children

Daniel Catovsky, MD, Protocol chair		Ph: 44-20-7808-2880 ext.2875 Email: daniel.catovsky@icr.ac.uk

Registry Information
Official Title		Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide
Trial Start Date		1999-10-09
Registered in ClinicalTrials.gov		NCT00004218
Date Submitted to PDQ		1999-12-03
Information Last Verified		2006-01-23

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