Clinical trial NCT00275054: Rituximab, Fludarabine, and Cyclophosphamide or Observation Alone in Treating Patients With Stage 0, Stage I, or Stage II Chronic Lymphocytic Leukemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Keywords: stage 0 chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
First posted: 2006-01-11
Enrollment: 825
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event-free survival
measure: Development of a new prognostic staging system
Secondary outcomes:
measure: Progression free survival
measure: Overall survival
measure: Time to progression to Binet stages B and C
measure: Time to treatment
measure: Quality of life
measure: Pharmacoeconomic analysis
measure: Overall response (complete and partial) rate in patients in the early treatment arm
measure: Percentage of patients achieving complete molecular remission in the early treatment arm
measure: Duration of response in patients in the early treatment arm
measure: Adverse events in patients in the early treatment arm
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Universitaetsklinik fuer Innere Medizin I
city: Amiens
country: France
facility: Centre Hospitalier Universitaire d'Amiens
city: Angers
country: France
facility: Centre Hospitalier Regional et Universitaire d'Angers
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy
city: Bobigny
country: France
facility: Hopital Avicenne
city: Caen
country: France
facility: CHU de Caen
city: Clermont-Ferrand
country: France
facility: CHR Clermont Ferrand, Hotel Dieu
city: Creteil
country: France
facility: Centre Hospitalier Universitaire Henri Mondor
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital de la Tronche
city: Le Mans
country: France
facility: Centre Jean Bernard
city: Lille
country: France
facility: Centre Hospital Universitaire Hop Huriez
city: Lyon
country: France
facility: Hopital Edouard Herriot - Lyon
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: CHU Pitie-Salpetriere
city: Paris
country: France
facility: Hopital Necker
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU - Robert Debre
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Toulouse
country: France
facility: CHU de Toulouse, Hotel Dieu
city: Vandoeuvre-Les-Nancy
country: France
facility: CHU de Nancy - Hopitaux de Brabois
city: Alsfeld
country: Germany
facility: Praxis fuer Innere Medizin Haematologie und Internistische Onkologie
city: Augsburg
country: Germany
facility: Hamatologische/Onkologische Gemeinschaftspraxis - Augsburg
city: Aurich
country: Germany
facility: Kreiskrankenhaus Aurich
city: Bamberg
country: Germany
facility: Klinikum am Bamberg
city: Berlin
country: Germany
facility: Internistische Gemeinschaftspraxis - Berlin
city: Berlin
country: Germany
facility: St. Hedwig Krankenhaus
city: Betzdorf
country: Germany
facility: Internistische Gemeinschaftspraxis Betzdorf
city: Bremen
country: Germany
facility: DIAKO Ev. Diakonie Krankenhaus gGmbH
city: Coesfeld
country: Germany
facility: Onkologische Schwerpunktpraxis at Facharzt fuer Innere Medizin
city: Cologne
country: Germany
facility: Praxis Fuer Haematologie Internistische Onkologie
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
city: Duesseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Onkologische Schwerpunkt Praxis
city: Eschweiler
country: Germany
facility: St. Antonius Hospital
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Forchheim
country: Germany
facility: Internistische Gemeinschaftspraxis - Forchheim
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt (Oder) GmbH
city: Friedberg
country: Germany
facility: Internistische Gemeinschaftspraxis - Friedberg
city: Fürstenzell
country: Germany
city: Garmisch-Partenkirchen
country: Germany
facility: Klinikum Garmisch - Partenkirchen GmbH
city: Germering
country: Germany
facility: Internistische Praxisgemeinschaft
city: Giessen
country: Germany
facility: Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie
city: Gottingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greifswald
country: Germany
facility: Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet
city: Greven
country: Germany
facility: Maria-Josef-Hospital Greven GmbH
city: Hagen
country: Germany
facility: St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
city: Halle
country: Germany
facility: Internistische Gemeinschaftspraxis - Halle
city: Halle
country: Germany
facility: Universitaetsklinikum Halle
city: Hannover
country: Germany
facility: Krankenhaus Siloah - Medizinische Klinik II
city: Hechingen
country: Germany
facility: Praxis Dr. med Freddy Henne
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Kassel
country: Germany
facility: Internistische Gemeinschaftspraxis - Kassel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Kronach
country: Germany
facility: Internistische Onkologische Praxis - Kronach
city: Landshut
country: Germany
facility: Internistische Praxis - Landshut
city: Lebach
country: Germany
facility: Caritas - Krakenhaus Lebach
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis - Leer
city: Magdeburg
country: Germany
facility: Staedtisches Klinikum Magdeburg - Altstadt
city: Mannheim
country: Germany
facility: Gemeinschaftspraxis
city: Minden
country: Germany
facility: Klinikum Minden
city: Moenchengladbach
country: Germany
facility: Haematologische Praxis - Moenchengladbach
city: Monchenglasbach/Rheydt
country: Germany
city: Munich
country: Germany
facility: Munich Oncologic Practice at Elisenhof
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar - Technische Universitaet Muenchen
city: Munich
country: Germany
facility: Hamatologie/Onkologie Praxisgemeinschaft - Muenchen
city: Munich
country: Germany
facility: Haematologische Schwerpunktpraxis
city: Mutlangen
country: Germany
facility: Klinikum Schwaebisch Gmuend Stauferklinik
city: Offenbach
country: Germany
facility: Internistische Gemeinschaftspraxis - Offenbach
city: Oldenburg
country: Germany
facility: Internistische Gemeinschaftspraxis - Oldenburg
city: Pforzheim
country: Germany
city: Russelsheim
country: Germany
facility: Internistische Schwerpunktpraxis
city: Saarbruecken
country: Germany
facility: Schwerpunktpraxis fuer Haematologie und Onkologie
city: Schwäbisch Hall
country: Germany
facility: Diakonie - Krankenhaus
city: Siegen
country: Germany
facility: St. Marien - Krankenhaus Siegen GMBH
city: Singen
country: Germany
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Stuttgart
country: Germany
facility: Diakonie Klinikum Stuttgart
city: Trier
country: Germany
facility: Onkologische Gemeinschaftspraxis - Trier
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Twistringen
country: Germany
facility: Praxis fuer Haematologie und Onkologie
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Vechta
country: Germany
facility: St. Marienhospital - Vechta
city: Worms
country: Germany
facility: Burkhard and Reimann Gemeinschaftspraxis
Study officials:
affiliation: Medizinische Universitaetsklinik I at the University of Cologne
name: Michael Hallek, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.