Clinical trial NCT00004218: Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
Official title: Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Medical Research Council
First posted: 2003-01-27
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Alvarez
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Ioannina
country: Greece
facility: University of Ioannina
city: Rio Patras
country: Greece
facility: University of Patras Medical School
city: Dublin
country: Ireland
facility: St. James' Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
city: Moscow
country: Russian Federation
facility: Russian Academy of Medical Sciences Cancer Research Center
city: Aylesbury-Buckinghamshire
country: United Kingdom
facility: Stoke Mandeville Hospital
state: England
city: Banbury
country: United Kingdom
facility: Horton Hospital
state: England
city: Basingstoke
country: United Kingdom
facility: North Hampshire Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Selly Oak Hospital at University Hospital NHS Trust
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Bradford
country: United Kingdom
facility: Bradford Hospitals NHS Trust
state: England
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
state: England
city: Carshalton
country: United Kingdom
facility: St Helier Hospital
state: England
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
state: England
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
state: England
city: Chichester
country: United Kingdom
facility: Saint Richards Hospital
state: England
city: Darlington
country: United Kingdom
facility: Darlington Memorial
state: England
city: Dartford Kent
country: United Kingdom
facility: Dartford & Gravesham NHS Trust, Joyce Green Hospital
state: England
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
state: England
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: England
city: Durham
country: United Kingdom
facility: Bishop Auckland Hospital
state: England
city: Epsom Surrey
country: United Kingdom
facility: Epsom General Hospital
state: England
city: Gateshead-Tyne and Wear
country: United Kingdom
facility: Queen Elizabeth Hospital
state: England
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
state: England
city: Gloucester
country: United Kingdom
facility: Gloucester Royal NHS Trust - Glouchester Royal Hospital
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
state: England
city: Hemel Hempstead
country: United Kingdom
facility: Hemel Hempstead General
state: England
city: High Wycombe
country: United Kingdom
facility: Institute of Oncology and Radiology of Serbia
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
state: England
city: Leeds
country: United Kingdom
facility: Clinical Trials and Research Unit of the University of Leeds
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen Hospitals
state: England
city: Liverpool
country: United Kingdom
facility: Walton General Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: London
country: United Kingdom
facility: Whipps Cross Hospital
state: England
city: London
country: United Kingdom
facility: Royal Free and University College Medical School
state: England
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust - London
state: England
city: Middlesex
country: United Kingdom
facility: West Middlesex Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Northern Cancer Network
state: England
city: Northampton
country: United Kingdom
facility: Northampton General Hospital NHS Trust
state: England
city: Nottinghamshire
country: United Kingdom
facility: Bassetlaw Hospital & Community Services NHS Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital NHS Trust
state: England
city: Orpington Kent
country: United Kingdom
facility: Farnborough Hospital
state: England
city: Otley
country: United Kingdom
facility: Wharfdale General Hospital
state: England
city: Pontefract West Yorkshire
country: United Kingdom
facility: Pontefract General Infirmary
state: England
city: Reading
country: United Kingdom
facility: Berkshire Cancer Centre at Royal Berkshire Hospital
state: England
city: Romford
country: United Kingdom
facility: Oldchurch Hospital
state: England
city: Rotherham
country: United Kingdom
facility: Rotherham District General Hospital - NHS Trust
state: England
city: Saint Leonards-on-Sea
country: United Kingdom
facility: Conquest Hospital
state: England
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
state: England
city: Southampton
country: United Kingdom
facility: Royal South Hants Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Stafford
country: United Kingdom
facility: Staffordshire General Hospital
state: England
city: Stoke-On-Trent
country: United Kingdom
facility: North Staffs Royal Infirmary
state: England
city: Surrey
country: United Kingdom
facility: St. Peter's Hospital NHS Trust
state: England
city: Torquay Devon
country: United Kingdom
facility: Torbay Hospital
state: England
city: West Bromwich
country: United Kingdom
facility: City Hospital - Birmingham
state: England
city: West Midlands
country: United Kingdom
facility: Good Hope Hospital Trust
state: England
city: Worthing
country: United Kingdom
facility: Worthing Hospital
state: England
city: York
country: United Kingdom
facility: Cancer Care Centre at York Hospital
state: England
city: Belfast
country: United Kingdom
facility: Belfast City Hospital Trust
state: Northern Ireland
city: Dundonald
country: United Kingdom
facility: Ulster Hospital
state: Northern Ireland
city: Portadown, Craigavon
country: United Kingdom
facility: Craigavon Area Hospital
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Airdrie
country: United Kingdom
facility: Monklands General Hospital
state: Scotland
city: Dumfries
country: United Kingdom
facility: Dumfries Royal Infirmary
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
state: Scotland
city: Glasgow
country: United Kingdom
facility: Southern General Hospital
state: Scotland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
state: Scotland
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Gwent
country: United Kingdom
facility: Nevill Hall Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: Singleton Hospital
state: Wales
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: Daniel Catovsky, MD
role: STUDY_CHAIR
References:
citation: 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.
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 CLL4 trial. J Clin Oncol. 2011 Jun 1;29(16):2223-9. doi: 10.1200/JCO.2010.32.0838. Epub 2011 Apr 11.
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 chemotherapy trial. Haematologica. 2011 Oct;96(10):1496-503. doi: 10.3324/haematol.2011.043471. Epub 2011 Jun 9.
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 of treatment allocation. Haematologica. 2010 Oct;95(10):1705-12. doi: 10.3324/haematol.2010.025338. Epub 2010 May 29.
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.1365-2141.2008.07407.x. Epub 2008 Oct 18.
citation: 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.
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, 2007.
citation: 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.