Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia - Full Text View

Sponsor:	Leukemia Research Fund
Collaborator:	Medical Research Council
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00004218

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. It is not yet known which regimen of chemotherapy is more effective for chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying chlorambucil to see how well it works compared to fludarabine and cyclophosphamide or fludarabine alone in treating patients with newly diagnosed chronic lymphocytic leukemia.

Condition	Intervention	Phase
Leukemia	Drug: chlorambucil Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: fludarabine phosphate Drug: prednisolone Drug: vincristine sulfate	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Primary Purpose: Treatment
Official Title:	Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

Resource links provided by NLM:

MedlinePlus related topics: Acute Lymphocytic Leukemia Cancer Chronic Lymphocytic Leukemia Leukemia

Drug Information available for: Cyclophosphamide Prednisolone Prednisolone acetate Depo-medrol Vincristine Fludarabine Doxorubicin Doxorubicin hydrochloride Fludarabine monophosphate Medrol veriderm Methylprednisolone Prednisolone sodium phosphate Chlorambucil Prednisolone Sodium Succinate Vincristine sulfate Methylprednisolone Sodium Succinate Methylprednisolone hemisuccinate 6-Methylprednisolone

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Study Start Date:

October 1999

Detailed Description:

OBJECTIVES:

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

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.

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

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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/mm^3)
- 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

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

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00004218

Show 86 Study Locations

Sponsors and Collaborators

Leukemia Research Fund

Medical Research Council

Investigators

Study Chair:

Daniel Catovsky, MD

Royal Marsden NHS Foundation Trust

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Else M, Cocks K, Crofts S, Wade R, Richards SM, Catovsky D, Smith AG. Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial. Leuk Lymphoma. 2011 Dec 15; [Epub ahead of print]

Gonzalez D, Martinez P, Wade R, Hockley S, Oscier D, Matutes E, Dearden CE, Richards SM, Catovsky D, Morgan GJ. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011 Jun 1;29(16):2223-9. Epub 2011 Apr 11.

Oscier D, Wade R, Davis Z, Morilla A, Best G, Richards S, Else M, Matutes E, Catovsky D; Chronic Lymphocytic Leukaemia Working Group, UK National Cancer Research Institute. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica. 2010 Oct;95(10):1705-12. Epub 2010 May 29.

Else M, Smith AG, Cocks K, Richards SM, Crofts S, Wade R, Catovsky D; on behalf of the UK NCRI CLL Trials Group. Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol. 2008 Oct 18; [Epub ahead of print]

Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9.

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.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wade R, Di Bernardo MC, Richards S, Rossi D, Crowther-Swanepoel D, Gaidano G, Oscier DG, Catovsky D, Houlston RS. Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. Haematologica. 2011 Oct;96(10):1496-503. Epub 2011 Jun 9.

ClinicalTrials.gov Identifier:	NCT00004218 History of Changes
Obsolete Identifiers:	NCT00222599
Other Study ID Numbers:	CDR0000067454, LRF-CLL4, LRG-MRC-LEUK-CLL4, EU-99030, MRC-LEUK-CLL4, EUDRACT-58585610, ISRCTN58585610
Study First Received:	January 28, 2000
Last Updated:	December 24, 2011
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
stage 0 chronic lymphocytic leukemia

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Chlorambucil
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Doxorubicin

Prednisolone
Methylprednisolone Hemisuccinate
Vincristine
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone phosphate
Vidarabine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents

ClinicalTrials.gov processed this record on February 12, 2012