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

May 21, 2019 updated by: German CLL Study Group

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • 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.

Secondary

  • 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.

Study Type

Interventional

Enrollment (Actual)

825

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • 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)

PATIENT CHARACTERISTICS:

  • 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

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy, radiotherapy, or antibody treatment
  • No other concurrent chemotherapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Fludura
Drug: Cyclophosphamide
cycles 1-6: 250 mg/m² i.v., d2-4, q28d
Other Names:
  • Endoxan
Biological: Rituximab

cycle1: 375 mg/m² i.v., d1, q28d

cycles 2-6: 500 mg/m² i.v., d1, q28d

Other Names:
  • Rituxan
  • Mabthera
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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free survival
Development of a new prognostic staging system

Secondary Outcome Measures

Outcome Measure
Overall survival
Quality of life
Progression free survival
Time to progression to Binet stages B and C
Time to treatment
Pharmacoeconomic analysis
Overall response (complete and partial) rate in patients in the early treatment arm
Percentage of patients achieving complete molecular remission in the early treatment arm
Duration of response in patients in the early treatment arm
Adverse events in patients in the early treatment arm

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

German CLL Study Group

Investigators

  • Principal Investigator: Michael Hallek, MD, Medizinische Universitaetsklinik I at the University of Cologne

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2005

Primary Completion (Actual)

July 1, 2007

Study Completion (Actual)

June 1, 2015

Study Registration Dates

First Submitted

January 10, 2006

First Submitted That Met QC Criteria

January 10, 2006

First Posted (Estimate)

January 11, 2006

Study Record Updates

Last Update Posted (Actual)

May 23, 2019

Last Update Submitted That Met QC Criteria

May 21, 2019

Last Verified

May 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLL7
  • EU-20559
  • ROCHE-GCLLSG-CLL7
  • 2005-003018-14 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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