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

NCT ID: NCT00275054

Last Updated: 2019-05-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 825 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-10-31
• Study Completion Date: 2015-06-30

Brief Summary

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.

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.

Conditions

Chronic Lymphocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

cycles 1-6: 25 mg/m² i.v., d2-4, q28d

Cyclophosphamide

Intervention Type: DRUG

cycles 1-6: 250 mg/m² i.v., d2-4, q28d

Rituximab

Intervention Type: BIOLOGICAL

cycle1: 375 mg/m² i.v., d1, q28d

cycles 2-6: 500 mg/m² i.v., d1, q28d

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).

Group Type: NO_INTERVENTION

No interventions assigned to this group

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).

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Fludarabine

cycles 1-6: 25 mg/m² i.v., d2-4, q28d

Intervention Type: DRUG

Cyclophosphamide

cycles 1-6: 250 mg/m² i.v., d2-4, q28d

Intervention Type: DRUG

Rituximab

cycle1: 375 mg/m² i.v., d1, q28d

cycles 2-6: 500 mg/m² i.v., d1, q28d

Intervention Type: BIOLOGICAL

Other Intervention Names

Fludura; Endoxan; Mabthera; Rituxan

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

German CLL Study Group

OTHER

Sponsor Role: lead

Principal Investigators

Michael Hallek, MD

Role: PRINCIPAL_INVESTIGATOR

Medizinische Universitaetsklinik I at the University of Cologne

Locations

Universitaetsklinik fuer Innere Medizin I

Vienna, , Austria

Centre Hospitalier Universitaire d'Amiens

Amiens, , France

Centre Hospitalier Regional et Universitaire d'Angers

Angers, , France

Centre Hospitalier Victor Dupouy

Argenteuil, , France

Hopital Avicenne

Bobigny, , France

CHU de Caen

Caen, , France

CHR Clermont Ferrand, Hotel Dieu

Clermont-Ferrand, , France

Centre Hospitalier Universitaire Henri Mondor

Créteil, , France

CHU de Grenoble - Hopital de la Tronche

Grenoble, , France

Centre Jean Bernard

Le Mans, , France

Centre Hospital Universitaire Hop Huriez

Lille, , France

Hopital Edouard Herriot - Lyon

Lyon, , France

Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes

Marseille, , France

Centre Hospitalier de Meaux

Meaux, , France

CHR Hotel Dieu

Nantes, , France

Hopital Saint-Louis

Paris, , France

CHU Pitie-Salpetriere

Paris, , France

Hopital Necker

Paris, , France

Hopital Haut Leveque

Pessac, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

CHU Poitiers

Poitiers, , France

CHU - Robert Debre

Reims, , France

Centre Henri Becquerel

Rouen, , France

Hopital Universitaire Hautepierre

Strasbourg, , France

CHU de Toulouse, Hotel Dieu

Toulouse, , France

CHU de Nancy - Hopitaux de Brabois

Vandœuvre-lès-Nancy, , France

Praxis fuer Innere Medizin Haematologie und Internistische Onkologie

Alsfeld, , Germany

Hamatologische/Onkologische Gemeinschaftspraxis - Augsburg

Augsburg, , Germany

Kreiskrankenhaus Aurich

Aurich, , Germany

Klinikum am Bamberg

Bamberg, , Germany

Internistische Gemeinschaftspraxis - Berlin

Berlin, , Germany

St. Hedwig Krankenhaus

Berlin, , Germany

Internistische Gemeinschaftspraxis Betzdorf

Betzdorf, , Germany

DIAKO Ev. Diakonie Krankenhaus gGmbH

Bremen, , Germany

Onkologische Schwerpunktpraxis at Facharzt fuer Innere Medizin

Coesfeld, , Germany

Praxis Fuer Haematologie Internistische Onkologie

Cologne, , Germany

Medizinische Universitaetsklinik I at the University of Cologne

Cologne, , Germany

Universitaetsklinikum Duesseldorf

Düsseldorf, , Germany

Helios Klinikum Erfurt

Erfurt, , Germany

Onkologische Schwerpunkt Praxis

Erlangen, , Germany

St. Antonius Hospital

Eschweiler, , Germany

Universitaetsklinikum Essen

Essen, , Germany

Internistische Gemeinschaftspraxis - Forchheim

Forchheim, , Germany

Klinikum Frankfurt (Oder) GmbH

Frankfurt (Oder), , Germany

Internistische Gemeinschaftspraxis - Friedberg

Friedberg, , Germany

Fürstenzell, , Germany

Klinikum Garmisch - Partenkirchen GmbH

Garmisch-Partenkirchen, , Germany

Internistische Praxisgemeinschaft

Germering, , Germany

Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie

Giessen, , Germany

Universitaetsklinikum Goettingen

Göttingen, , Germany

Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet

Greifswald, , Germany

Maria-Josef-Hospital Greven GmbH

Greven, , Germany

St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH

Hagen, , Germany

Internistische Gemeinschaftspraxis - Halle

Halle, , Germany

Universitaetsklinikum Halle

Halle, , Germany

Krankenhaus Siloah - Medizinische Klinik II

Hanover, , Germany

Praxis Dr. med Freddy Henne

Hechingen, , Germany

Universitatsklinikum Heidelberg

Heidelberg, , Germany

Westpfalz-Klinikum GmbH

Kaiserslautern, , Germany

Internistische Gemeinschaftspraxis - Kassel

Kassel, , Germany

University Hospital Schleswig-Holstein - Kiel Campus

Kiel, , Germany

Internistische Onkologische Praxis - Kronach

Kronach, , Germany

Internistische Praxis - Landshut

Landshut, , Germany

Caritas - Krakenhaus Lebach

Lebach, , Germany

Onkologische Schwerpunktpraxis - Leer

Leer, , Germany

Staedtisches Klinikum Magdeburg - Altstadt

Magdeburg, , Germany

Gemeinschaftspraxis

Mannheim, , Germany

Klinikum Minden

Minden, , Germany

Monchenglasbach/Rheydt, , Germany

Haematologische Praxis - Moenchengladbach

Mönchengladbach, , Germany

Munich Oncologic Practice at Elisenhof

Munich, , Germany

Klinikum Rechts Der Isar - Technische Universitaet Muenchen

Munich, , Germany

Hamatologie/Onkologie Praxisgemeinschaft - Muenchen

Munich, , Germany

Haematologische Schwerpunktpraxis

Munich, , Germany

Klinikum Schwaebisch Gmuend Stauferklinik

Mutlangen, , Germany

Internistische Gemeinschaftspraxis - Offenbach

Offenbach, , Germany

Internistische Gemeinschaftspraxis - Oldenburg

Oldenburg, , Germany

Pforzheim, , Germany

Internistische Schwerpunktpraxis

Rüsselsheim am Main, , Germany

Schwerpunktpraxis fuer Haematologie und Onkologie

Saarbrücken, , Germany

Diakonie - Krankenhaus

Schwäbisch Hall, , Germany

St. Marien - Krankenhaus Siegen GMBH

Siegen, , Germany

Singen, , Germany

Robert-Bosch-Krankenhaus

Stuttgart, , Germany

Diakonie Klinikum Stuttgart

Stuttgart, , Germany

Onkologische Gemeinschaftspraxis - Trier

Trier, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Praxis fuer Haematologie und Onkologie

Twistringen, , Germany

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm

Ulm, , Germany

St. Marienhospital - Vechta

Vechta, , Germany

Burkhard and Reimann Gemeinschaftspraxis

Worms, , Germany

Countries

Austria; France; Germany

References

Sachanas S, Pangalis GA, Fink AM, Bahlo J, Fischer K, Levidou G, Kyrtsonis MC, Bartzi V, Vassilakopoulos TP, Kalpadakis C, Koulieris E, Moschogiannis M, Yiakoumis X, Tsirkinidis P, Angelopoulou MK, Eichhorst B, Hallek M. Small Lymphocytic Lymphoma: Analysis of Two Cohorts Including Patients in Clinical Trials of the German Chronic Lymphocytic Leukemia Study Group (GCLLSG) or in "Real-Life" Outside of Clinical Trials. Anticancer Res. 2019 May;39(5):2591-2598. doi: 10.21873/anticanres.13382.

Reference Type: BACKGROUND

PMID: 31092457 (View on PubMed)

Herling CD, Cymbalista F, Gross-Ophoff-Muller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Lepretre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Dohner H, Leblond V, Kneba M, Letestu R, Bottcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. doi: 10.1038/s41375-020-0747-7. Epub 2020 Feb 18.

Reference Type: DERIVED

PMID: 32071431 (View on PubMed)

Other Identifiers

EU-20559

Identifier Type: -

Identifier Source: secondary_id

ROCHE-GCLLSG-CLL7

Identifier Type: -

Identifier Source: secondary_id

2005-003018-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLL7

Identifier Type: -

Identifier Source: org_study_id