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Rituximab, Fludarabine, and Cyclophosphamide or Observation Alone in Treating Patients With Stage 0, Stage I, or Stage II Chronic Lymphocytic Leukemia

This study has been completed.
Information provided by:
German CLL Study Group Identifier:
First received: January 10, 2006
Last updated: September 30, 2016
Last verified: September 2016

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving rituximab together with fludarabine and cyclophosphamide is more effective than observation alone in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying rituximab, fludarabine, and cyclophosphamide to see how well they work compared to observation alone in treating patients with stage 0, stage I, or stage II B-cell chronic lymphocytic leukemia.

Condition Intervention Phase
Chronic Lymphocytic Leukemia
Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Rituximab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase III Trial Comparing Early Treatment With Fludarabine/Cyclophosphamide + Rituximab Versus Deferred Treatment in Untreated Binet Stage A Patients With CLL and High Risk of Progression

Resource links provided by NLM:

Further study details as provided by German CLL Study Group:

Primary Outcome Measures:
  • Event-free survival [ Designated as safety issue: No ]
  • Development of a new prognostic staging system [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression free survival [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Time to progression to Binet stages B and C [ Designated as safety issue: No ]
  • Time to treatment [ Designated as safety issue: No ]
  • Quality of life [ Designated as safety issue: No ]
  • Pharmacoeconomic analysis [ Designated as safety issue: No ]
  • Overall response (complete and partial) rate in patients in the early treatment arm [ Designated as safety issue: No ]
  • Percentage of patients achieving complete molecular remission in the early treatment arm [ Designated as safety issue: No ]
  • Duration of response in patients in the early treatment arm [ Designated as safety issue: No ]
  • Adverse events in patients in the early treatment arm [ Designated as safety issue: Yes ]

Enrollment: 825
Study Start Date: October 2005
Study Completion Date: June 2015
Primary Completion Date: July 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I (FCR)
Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort I receive Fludarabine, Cyclophosphamide and Rituximab (FCR) chemoimmunotherapy.
Drug: Fludarabine
cycles 1-6: 25 mg/m² i.v., d2-4, q28d
Other Name: Fludura
Drug: Cyclophosphamide
cycles 1-6: 250 mg/m² i.v., d2-4, q28d
Other Name: Endoxan
Biological: Rituximab

cycle1: 375 mg/m² i.v., d1, q28d

cycles 2-6: 500 mg/m² i.v., d1, q28d

Other Names:
  • Mabthera
  • Rituxan
No Intervention: Cohort II (W&W)
Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort II receive no treatment at all (watch & wait).
No Intervention: Cohort III (W&W)
Patients with less than 2 risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) are assigned directly to cohort III and receive no treatment at all (watch & wait).

Detailed Description:



  • Compare the effect, in terms of event-free survival, of deferred versus immediate treatment with rituximab, fludarabine, and cyclophosphamide in patients with previously untreated Binet stage A chronic lymphocytic leukemia at high risk for disease progression.
  • Investigate and define a new prognostic staging system for patients with Binet stage A chronic lymphocytic leukemia.


  • Compare the time to progression to Binet stages B and C in patients treated with these regimens.
  • Compare the overall and progression-free survival of patients treated with these regimens.
  • Compare the quality of life of patients treated with these regimens.
  • Compare the time to treatment in patients treated with these regimens.
  • Analyze the pharmacoeconomics of these regimens in these patients.
  • Determine the overall response rate (partial and complete) in patients included in the early treatment arm.
  • For patients included in the early treatment arm in complete remission, determine the percentage achieving complete molecular remission using the clone-specific CDR-III region as follow-up parameter.
  • Determine the duration of response in patients included in the early treatment arm.
  • Determine any adverse events related to treatment/safety of treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk factor profile (< 2 risk factors [low risk] vs ≥ 2 risk factors [high risk]). Low-risk patients are assigned to arm II. High-risk patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive rituximab IV on day 1, fludarabine IV on days 1-3, and cyclophosphamide IV on days 1-3. Treatment repeats every 28 days for up to 6 courses.
  • Arm II: Patients undergo observation only until disease progression.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


  • Established diagnosis of B-cell chronic lymphocytic leukemia

    • First diagnosis within 12 months before inclusion in study
    • Previously untreated disease
  • Binet stage A disease (Rai stage 0, I, or II)


  • Life expectancy > 6 months
  • ECOG performance status 0-2
  • Willingness to accept contraception (if randomized to arm I) for the duration of therapy and 12 months thereafter
  • Negative serum pregnancy test
  • All parameters for risk stratification (lymphocyte doubling time, cytogenetics, unmutated IgVH, and serum thymidine kinase level > 10) present


  • No prior chemotherapy, radiotherapy, or antibody treatment
  • No other concurrent chemotherapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00275054

  Hide Study Locations
Universitaetsklinik fuer Innere Medizin I
Vienna, Austria, A-1090
Centre Hospitalier Universitaire d'Amiens
Amiens, France, 80054
Centre Hospitalier Regional et Universitaire d'Angers
Angers, France, 49033
Centre Hospitalier Victor Dupouy
Argenteuil, France, 95107
Hopital Avicenne
Bobigny, France, 93009
CHU de Caen
Caen, France, 14033
CHR Clermont Ferrand, Hotel Dieu
Clermont-Ferrand, France, 63058
Centre Hospitalier Universitaire Henri Mondor
Creteil, France, 94000
CHU de Grenoble - Hopital de la Tronche
Grenoble, France, 38043
Centre Jean Bernard
Le Mans, France, 72000
Centre Hospital Universitaire Hop Huriez
Lille, France, 59037
Hopital Edouard Herriot - Lyon
Lyon, France, 69437
Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
Marseille, France, 13273
Centre Hospitalier de Meaux
Meaux, France, 77104
CHR Hotel Dieu
Nantes, France, 44093
Hopital Saint-Louis
Paris, France, 75475
CHU Pitie-Salpetriere
Paris, France, 75651
Hopital Necker
Paris, France, 75743
Hopital Haut Leveque
Pessac, France, 33604
Centre Hospitalier Lyon Sud
Pierre Benite, France, 69495
CHU Poitiers
Poitiers, France, 86021
CHU - Robert Debre
Reims, France, 51092
Centre Henri Becquerel
Rouen, France, 76038
Hopital Universitaire Hautepierre
Strasbourg, France, 67098
CHU de Toulouse, Hotel Dieu
Toulouse, France, 31059
CHU de Nancy - Hopitaux de Brabois
Vandoeuvre-Les-Nancy, France, 54511
Praxis fuer Innere Medizin Haematologie und Internistische Onkologie
Alsfeld, Germany, 36304
Hamatologische/Onkologische Gemeinschaftspraxis - Augsburg
Augsburg, Germany, 86150
Kreiskrankenhaus Aurich
Aurich, Germany, 26603
Klinikum am Bamberg
Bamberg, Germany, 96049
Internistische Gemeinschaftspraxis - Berlin
Berlin, Germany, 13347
St. Hedwig Krankenhaus
Berlin, Germany, D-10115
Internistische Gemeinschaftspraxis Betzdorf
Betzdorf, Germany, D-57518
DIAKO Ev. Diakonie Krankenhaus gGmbH
Bremen, Germany, D-28239
Onkologische Schwerpunktpraxis at Facharzt fuer Innere Medizin
Coesfeld, Germany, 48653
Praxis Fuer Haematologie Internistische Onkologie
Cologne, Germany, D-50677
Medizinische Universitaetsklinik I at the University of Cologne
Cologne, Germany, D-50924
Universitaetsklinikum Duesseldorf
Duesseldorf, Germany, D-40225
Helios Klinikum Erfurt
Erfurt, Germany, 99012
Onkologische Schwerpunkt Praxis
Erlangen, Germany, D-91052
St. Antonius Hospital
Eschweiler, Germany, DOH-52249
Universitaetsklinikum Essen
Essen, Germany, D-45122
Internistische Gemeinschaftspraxis - Forchheim
Forchheim, Germany, 91301
Klinikum Frankfurt (Oder) GmbH
Frankfurt (Oder), Germany, D-15236
Internistische Gemeinschaftspraxis - Friedberg
Friedberg, Germany, 86316
Fuerstenzell, Germany, 94981
Klinikum Garmisch - Partenkirchen GmbH
Garmisch-Partenkirchen, Germany, D-82467
Internistische Praxisgemeinschaft
Germering, Germany, 82110
Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie
Giessen, Germany, 35392
Universitaetsklinikum Goettingen
Gottingen, Germany, D-37075
Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet
Greifswald, Germany, D-17475
Maria-Josef-Hospital Greven GmbH
Greven, Germany, 48268
St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
Hagen, Germany, D-58095
Internistische Gemeinschaftspraxis - Halle
Halle, Germany, 06110
Universitaetsklinikum Halle
Halle, Germany, D-06120
Krankenhaus Siloah - Medizinische Klinik II
Hannover, Germany, D-30449
Praxis Dr. med Freddy Henne
Hechingen, Germany, D-72379
Universitatsklinikum Heidelberg
Heidelberg, Germany, D-69120
Westpfalz-Klinikum GmbH
Kaiserslautern, Germany, D-67653
Internistische Gemeinschaftspraxis - Kassel
Kassel, Germany, D-34117
University Hospital Schleswig-Holstein - Kiel Campus
Kiel, Germany, D-24116
Internistische Onkologische Praxis - Kronach
Kronach, Germany, 96317
Internistische Praxis - Landshut
Landshut, Germany, 84028
Caritas - Krakenhaus Lebach
Lebach, Germany, 66822
Onkologische Schwerpunktpraxis - Leer
Leer, Germany, D-26789
Staedtisches Klinikum Magdeburg - Altstadt
Magdeburg, Germany, D-39104
Mannheim, Germany, D-68161
Klinikum Minden
Minden, Germany, D-32423
Haematologische Praxis - Moenchengladbach
Moenchengladbach, Germany, D-41239
Monchenglasbach/Rheydt, Germany, D-41239
Munich Oncologic Practice at Elisenhof
Munich, Germany, D-80335
Klinikum Rechts Der Isar - Technische Universitaet Muenchen
Munich, Germany, D-81241
Hamatologie/Onkologie Praxisgemeinschaft - Muenchen
Munich, Germany, D-81245
Haematologische Schwerpunktpraxis
Munich, Germany, D-81679
Klinikum Schwaebisch Gmuend Stauferklinik
Mutlangen, Germany, D-73557
Internistische Gemeinschaftspraxis - Offenbach
Offenbach, Germany, D-63065
Internistische Gemeinschaftspraxis - Oldenburg
Oldenburg, Germany, D-26121
Pforzheim, Germany, 75179
Internistische Schwerpunktpraxis
Russelsheim, Germany, 65428
Schwerpunktpraxis fuer Haematologie und Onkologie
Saarbruecken, Germany, 66113
Diakonie - Krankenhaus
Schwaebisch Hall, Germany, 74523
St. Marien - Krankenhaus Siegen GMBH
Siegen, Germany, D-57072
Singen, Germany, D-78224
Stuttgart, Germany, 70376
Diakonie Klinikum Stuttgart
Stuttgart, Germany, D-70176
Onkologische Gemeinschaftspraxis - Trier
Trier, Germany, 54290
Universitaetsklinikum Tuebingen
Tuebingen, Germany, D-72076
Praxis fuer Haematologie und Onkologie
Twistringen, Germany, D-27239
Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
Ulm, Germany, D-89081
St. Marienhospital - Vechta
Vechta, Germany, D-49377
Burkhard and Reimann Gemeinschaftspraxis
Worms, Germany, DOH-67547
Sponsors and Collaborators
German CLL Study Group
Principal Investigator: Michael Hallek, MD Medizinische Universitaetsklinik I at the University of Cologne
  More Information

Additional Information: Identifier: NCT00275054     History of Changes
Other Study ID Numbers: CLL7  EU-20559  ROCHE-GCLLSG-CLL7  2005-003018-14 
Study First Received: January 10, 2006
Last Updated: September 30, 2016
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Germany: Paul-Ehrlich-Institut
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by German CLL Study Group:
stage 0 chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents processed this record on October 21, 2016