Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

Leukemia Clinical Trial

Official title:

Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00004218
• Other study ID #: CDR0000067454
• Secondary ID: LRF-CLL4LRG-MRC-
• Status: Completed
• Phase: Phase 3
• First received: January 28, 2000
• Last updated: December 17, 2013
• Start date: October 1999
• Est. completion date: July 2007

Study information

• Verified date: January 2006
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• 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. 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.

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.

Other known NCT identifiers

• NCT00222599

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• chlorambucil

• cyclophosphamide

• doxorubicin hydrochloride

• fludarabine phosphate

• prednisolone

• vincristine sulfate

Locations

Country	Name	City	State
Argentina	Hospital Alvarez	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires
Croatia	University Hospital Rebro	Zagreb
Greece	University of Ioannina	Ioannina
Greece	University of Patras Medical School	Rio Patras
Ireland	St. James' Hospital	Dublin
Ireland	Galway University Hospital	Galway
Italy	Ospedali Riuniti di Bergamo	Bergamo
New Zealand	Canterbury Health Laboratories	Christchurch
Russian Federation	Russian Academy of Medical Sciences Cancer Research Center	Moscow
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Monklands General Hospital	Airdrie	Scotland
United Kingdom	Stoke Mandeville Hospital	Aylesbury-Buckinghamshire	England
United Kingdom	Horton Hospital	Banbury	England
United Kingdom	Ysbyty Gwynedd	Bangor	Wales
United Kingdom	North Hampshire Hospital	Basingstoke	England
United Kingdom	Belfast City Hospital Trust	Belfast	Northern Ireland
United Kingdom	Birmingham Heartlands Hospital	Birmingham	England
United Kingdom	Selly Oak Hospital at University Hospital NHS Trust	Birmingham	England
United Kingdom	Blackpool Victoria Hospital	Blackpool	England
United Kingdom	Royal Bournemouth Hospital	Bournemouth	England
United Kingdom	Bradford Hospitals NHS Trust	Bradford	England
United Kingdom	Royal Sussex County Hospital	Brighton	England
United Kingdom	Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust	Cambridge	England
United Kingdom	St Helier Hospital	Carshalton	England
United Kingdom	Countess of Chester Hospital	Chester	England
United Kingdom	Chesterfield Royal Hospital	Chesterfield	England
United Kingdom	Saint Richards Hospital	Chichester	England
United Kingdom	Darlington Memorial	Darlington	England
United Kingdom	Dartford & Gravesham NHS Trust, Joyce Green Hospital	Dartford Kent	England
United Kingdom	Doncaster Royal Infirmary	Doncaster	England
United Kingdom	Russells Hall Hospital	Dudley	England
United Kingdom	Dumfries Royal Infirmary	Dumfries	Scotland
United Kingdom	Ulster Hospital	Dundonald	Northern Ireland
United Kingdom	Bishop Auckland Hospital	Durham	England
United Kingdom	Western General Hospital	Edinburgh	Scotland
United Kingdom	Epsom General Hospital	Epsom Surrey	England
United Kingdom	Queen Elizabeth Hospital	Gateshead	England
United Kingdom	Queen Elizabeth Hospital	Gateshead-Tyne and Wear	England
United Kingdom	Southern General Hospital	Glasgow	Scotland
United Kingdom	Gloucester Royal NHS Trust - Glouchester Royal Hospital	Gloucester	England
United Kingdom	St. Luke's Cancer Centre at Royal Surrey County Hospital	Guildford	England
United Kingdom	Nevill Hall Hospital	Gwent	Wales
United Kingdom	Harrogate District Hospital	Harrogate	England
United Kingdom	Hemel Hempstead General	Hemel Hempstead	England
United Kingdom	Institute of Oncology and Radiology of Serbia	High Wycombe	England
United Kingdom	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England
United Kingdom	Hull Royal Infirmary	Hull	England
United Kingdom	Raigmore Hospital	Inverness	Scotland
United Kingdom	Victoria Hospital	Kirkcaldy	Scotland
United Kingdom	Clinical Trials and Research Unit of the University of Leeds	Leeds	England
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Royal Liverpool and Broadgreen Hospitals	Liverpool	England
United Kingdom	Walton General Hospital	Liverpool	England
United Kingdom	Guy's and St. Thomas' Hospitals NHS Foundation Trust	London	England
United Kingdom	Royal Free and University College Medical School	London	England
United Kingdom	Royal Marsden NHS Foundation Trust - London	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	Whipps Cross Hospital	London	England
United Kingdom	West Middlesex Hospital	Middlesex	England
United Kingdom	Northern Cancer Network	Newcastle-Upon-Tyne	England
United Kingdom	Northampton General Hospital NHS Trust	Northampton	England
United Kingdom	Nottingham City Hospital NHS Trust	Nottingham	England
United Kingdom	Bassetlaw Hospital & Community Services NHS Trust	Nottinghamshire	England
United Kingdom	Farnborough Hospital	Orpington Kent	England
United Kingdom	Wharfdale General Hospital	Otley	England
United Kingdom	Royal Alexandra Hospital	Paisley	Scotland
United Kingdom	Pontefract General Infirmary	Pontefract West Yorkshire	England
United Kingdom	Craigavon Area Hospital	Portadown, Craigavon	Northern Ireland
United Kingdom	Berkshire Cancer Centre at Royal Berkshire Hospital	Reading	England
United Kingdom	Oldchurch Hospital	Romford	England
United Kingdom	Rotherham District General Hospital - NHS Trust	Rotherham	England
United Kingdom	Conquest Hospital	Saint Leonards-on-Sea	England
United Kingdom	Scunthorpe General Hospital	Scunthorpe	England
United Kingdom	Royal South Hants Hospital	Southampton	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Staffordshire General Hospital	Stafford	England
United Kingdom	North Staffs Royal Infirmary	Stoke-On-Trent	England
United Kingdom	St. Peter's Hospital NHS Trust	Surrey	England
United Kingdom	Singleton Hospital	Swansea	Wales
United Kingdom	Torbay Hospital	Torquay Devon	England
United Kingdom	City Hospital - Birmingham	West Bromwich	England
United Kingdom	Good Hope Hospital Trust	West Midlands	England
United Kingdom	Worthing Hospital	Worthing	England
United Kingdom	Cancer Care Centre at York Hospital	York	England

Sponsors (2)

Lead Sponsor	Collaborator
Leukemia Research Fund	Medical Research Council

Countries where clinical trial is conducted

Argentina,  Croatia,  Greece,  Ireland,  Italy,  New Zealand,  Russian Federation,  United Kingdom, 

References & Publications (7)

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 ( — View Citation

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, 2

Else M, Cocks K, Crofts S, Wade R, Richards SM, Catovsky D, Smith AG; UK National Cancer Research Institute (NCRI) Chronic Lymphocytic Leukaemia Trials Group. Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized — View Citation

Else M, Smith AG, Cocks K, Richards SM, Crofts S, Wade R, Catovsky D. Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol. 2008 Dec;143(5):690-7. doi: 10.1111/j.1365 — View Citation

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 — View Citation

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 — View Citation

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 chemoth — View Citation