Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
NCT ID: NCT00004218
Last Updated: 2013-12-18
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE3
INTERVENTIONAL
1999-10-31
2007-07-31
Brief Summary
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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.
Detailed Description
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* 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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
TREATMENT
Interventions
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chlorambucil
cyclophosphamide
doxorubicin hydrochloride
fludarabine phosphate
prednisolone
vincristine sulfate
Eligibility Criteria
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Inclusion Criteria
* 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
ALL
No
Sponsors
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Medical Research Council
OTHER_GOV
Leukemia Research Fund
OTHER
Principal Investigators
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Daniel Catovsky, MD
Role: STUDY_CHAIR
Royal Marsden NHS Foundation Trust
Locations
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Hospital Italiano de Buenos Aires
Buenos Aires, , Argentina
Hospital Alvarez
Buenos Aires, , Argentina
University Hospital Rebro
Zagreb, , Croatia
University of Ioannina
Ioannina, , Greece
University of Patras Medical School
Rio Patras, , Greece
St. James' Hospital
Dublin, , Ireland
Galway University Hospital
Galway, , Ireland
Ospedali Riuniti di Bergamo
Bergamo, , Italy
Canterbury Health Laboratories
Christchurch, , New Zealand
Russian Academy of Medical Sciences Cancer Research Center
Moscow, , Russia
Stoke Mandeville Hospital
Aylesbury-Buckinghamshire, England, United Kingdom
Horton Hospital
Banbury, England, United Kingdom
North Hampshire Hospital
Basingstoke, England, United Kingdom
Selly Oak Hospital at University Hospital NHS Trust
Birmingham, England, United Kingdom
Birmingham Heartlands Hospital
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
Bishop Auckland Hospital
Durham, England, 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
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
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
Clinical Trials and Research Unit of the University of Leeds
Leeds, England, United Kingdom
Leicester Royal Infirmary
Leicester, England, United Kingdom
Royal Liverpool and Broadgreen Hospitals
Liverpool, England, United Kingdom
Walton General Hospital
Liverpool, England, United Kingdom
Aintree University Hospital
Liverpool, England, United Kingdom
Whipps Cross Hospital
London, England, United Kingdom
Royal Free and University College Medical School
London, England, United Kingdom
Guy's and St. Thomas' Hospitals NHS Foundation Trust
London, England, United Kingdom
St. George's Hospital
London, England, United Kingdom
Royal Marsden NHS Foundation Trust - London
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
Pontefract General Infirmary
Pontefract West Yorkshire, England, 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
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, United Kingdom
Belfast City Hospital Trust
Belfast, Northern Ireland, United Kingdom
Ulster Hospital
Dundonald, Northern Ireland, United Kingdom
Craigavon Area Hospital
Portadown, Craigavon, Northern Ireland, United Kingdom
Aberdeen Royal Infirmary
Aberdeen, Scotland, United Kingdom
Monklands General Hospital
Airdrie, Scotland, United Kingdom
Dumfries Royal Infirmary
Dumfries, Scotland, United Kingdom
Western General Hospital
Edinburgh, Scotland, United Kingdom
Southern General Hospital
Glasgow, Scotland, United Kingdom
Raigmore Hospital
Inverness, Scotland, United Kingdom
Victoria Hospital
Kirkcaldy, Scotland, United Kingdom
Royal Alexandra Hospital
Paisley, Scotland, United Kingdom
Ysbyty Gwynedd
Bangor, Wales, United Kingdom
Nevill Hall Hospital
Gwent, Wales, United Kingdom
Singleton Hospital
Swansea, Wales, United Kingdom
Countries
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References
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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 LRF CLL4 trial. Leuk Lymphoma. 2012 Jul;53(7):1289-98. doi: 10.3109/10428194.2011.649479. Epub 2012 Mar 1.
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. doi: 10.1200/JCO.2010.32.0838. Epub 2011 Apr 11.
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. doi: 10.3324/haematol.2011.043471. Epub 2011 Jun 9.
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. doi: 10.3324/haematol.2010.025338. Epub 2010 May 29.
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.1365-2141.2008.07407.x. Epub 2008 Oct 18.
Catovsky D, Richards S, Matutes E, Oscier D, Dyer M, 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):230-239. doi: 10.1016/S0140-6736(07)61125-8.
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.
Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, Dyer M, Matutes E, Gonzalez D, Taylor AM, Moss P, Thomas P, Oscier D, Stankovic T. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol. 2012 Dec 20;30(36):4524-32. doi: 10.1200/JCO.2011.41.0852. Epub 2012 Oct 22.
Other Identifiers
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LRF-CLL4
Identifier Type: -
Identifier Source: secondary_id
LRG-MRC-LEUK-CLL4
Identifier Type: -
Identifier Source: secondary_id
EU-99030
Identifier Type: -
Identifier Source: secondary_id
MRC-LEUK-CLL4
Identifier Type: -
Identifier Source: secondary_id
EUDRACT-58585610
Identifier Type: -
Identifier Source: secondary_id
ISRCTN58585610
Identifier Type: -
Identifier Source: secondary_id
CDR0000067454
Identifier Type: -
Identifier Source: org_study_id
NCT00222599
Identifier Type: -
Identifier Source: nct_alias