Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia

Leukemia Clinical Trial

— CLL-8  

Official title:

Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Chemotherapy With Fludarabine and Cyclophosphamide (FC) Alone in Patients With Previously Untreated Chronic Lymphocytic Leukaemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00281918
• Other study ID #: CDR0000454560
• Secondary ID: GCLLSG-CLL-8EU-2
• Status: Completed
• Phase: Phase 3
• First received: January 24, 2006
• Last updated: September 9, 2013
• Start date: July 2003
• Est. completion date: October 2011

Study information

• Verified date: September 2013
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared to fludarabine and cyclophosphamide in treating patients with B-cell chronic lymphocytic leukemia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 817
• Est. completion date: October 2011
• Est. primary completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria

• Meets 1 of the following criteria:

• Binet stage C disease

• Binet stage B disease AND = 1 of the following signs or symptoms*:

• B symptoms (night sweats, weight loss = 10% within the previous 6 months, fevers > 38°C or 100.4°F for = 2 weeks without evidence of infection), or constitutional symptoms (fatigue)

• Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count > 50 G/I)

• Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia

• Massive, progressive or painful splenomegaly or hypersplenism

• Massive lymph nodes or lymph node clusters (> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy

• Occurrence of symptomatic hyperviscosity problems at leukocyte counts > 200 G/I (symptomatic leukostasis) NOTE: * Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility

• No Binet stage A disease

• No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Cumulative Illness Rating Scale (CIRS) score > 6

• Life expectancy > 6 months

• Bilirubin = 2 times upper limit of normal (ULN)

• Alkaline phosphatase and transaminases = 2 times ULN

• Creatinine clearance = 70 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 2 months after study treatment

• No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs

• No cerebral dysfunction that precludes chemotherapy

• No active bacterial, viral, or fungal infection

• No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia

• No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery

• No medical or psychological condition that would preclude study therapy

• No concurrent disease that requires prolonged (> 1 month) therapy involving glucocorticoids

PRIOR CONCURRENT THERAPY:

• No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, B-Cell
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Rituximab
Intravenous repeating dose
• Cyclophosphamide
Intravenous repeating dose
• Fludarabine Phosphate
Intravenous repeating dose

Locations

Country	Name	City	State
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Peter MacCallum Cancer Centre	East Melbourne	Victoria
Australia	Frankston Hospital	Frankston	Victoria
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Westmead Institute for Cancer Research at Westmead Hospital	Westmead - Wentworthville	New South Wales
Austria	Hanuschkrankenhaus	Vienna
Austria	Rudolfinerhaus	Vienna
Austria	Allg. Krankenhaus der Stadt Wien Universitaets-Kinderklinik	Wien
Belgium	AZ Sint-Jan	Brugge
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Institut Jules Bordet	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	U.Z. Gasthuisberg	Leuven
Belgium	Clinique Universitaire De Mont-Godinne	Mont-Godinne Yvoir
Czech Republic	Masaryk University Hospital	Brno
Czech Republic	Fakultni Nemocnice Hradec Kralove	Hradec Kralove
Czech Republic	University Hospital - Olomouc	Olomouc
Czech Republic	University Hospital in Pilsen - Lochotin	Pilsen-Lochotin
Czech Republic	First Medical Clinic of Charles University Hospital	Prague
Denmark	Copenhagen County Herlev University Hospital	Copenhagen
Denmark	Vejle Sygehus	Vejle
France	Hopital Louis Pasteur	Colmar
France	Hopital Andre Mignot	Le Chesnay
France	Centre Leon Berard	Lyon
France	Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes	Marseille
France	Centre Hospitalier Universitaire de Rennes	Rennes
France	Institut de Cancerologie de la Loire	Saint Priest en Jarez
Germany	Praxis Fur Hamatologie und Onkologie Ahaus	Ahaus
Germany	Gemeinschaftspraxis Fuer Innere Medizin, Haematologie Und Internistische Onkologie	Ansbach
Germany	Hamatologische/Onkologische Gemeinschaftspraxis - Augsburg	Augsburg
Germany	Klinikum Augsburg	Augsburg
Germany	Humaine - Clinic	Bad Saarow
Germany	Internistische Praxis - Bayreuth	Bayreuth
Germany	Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin	Berlin
Germany	Internistische Gemeinschaftspraxis - Berlin	Berlin
Germany	Onkologische Schwerpunktpraxis Bielefeld	Bielefeld
Germany	Krankenhaus Bietigheim	Bietigheim
Germany	Augusta-Kranken-Anstalt gGmbH	Bochum
Germany	Marienhospital Bottrop gGmbH	Bottrop
Germany	DIAKO Ev. Diakonie Krankenhaus gGmbH	Bremen
Germany	Krankenhaus Burglengenfeld	Burglengenfeld
Germany	Onkologische Schwerpunktpraxis at Facharzt fuer Innere Medizin	Coesfeld
Germany	Medizinische Universitaetsklinik I at the University of Cologne	Cologne
Germany	Praxis Fuer Haematologie Internistische Onkologie	Cologne
Germany	Onkologische Schwerpunktpraxis	Cottbus
Germany	Onkologische Gemeinschaftspraxis - Dresden	Dresden
Germany	Universitaetsklinikum Duesseldorf	Duesseldorf
Germany	Florence-Nightingale-Krankenhause, Deaconess Kaiserswerth	Dusseldorf
Germany	Internistische Praxis - Dusseldorf	Dusseldorf
Germany	Krankenhaus Benrath	Dusseldorf
Germany	St. Georg Klinikum Eisenach GmbH	Eisenach
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Internistiche Praxis	Erfurt
Germany	Onkologische Schwerpunkt Praxis	Erlangen
Germany	St. Antonius Hospital	Eschweiler
Germany	Evangelisches Krankenhaus Essen Werden	Essen
Germany	Universitaetsklinikum Essen	Essen
Germany	Staedtische Kliniken Esslingen	Esslingen
Germany	Internistische Gemeinschaftspraxis - Forchheim	Forchheim
Germany	Staedtische Kliniken Frankfurt am Main - Hoechst	Frankfurt
Germany	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)
Germany	Gemeinschaftspraxis - Freiburg	Freiburg
Germany	Klinikum Garmisch - Partenkirchen GmbH	Garmisch-Partenkirchen
Germany	Internistische Praxis - Gerlingen	Gerlingen
Germany	Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie	Giessen
Germany	Universitaetsklinikum Goettingen	Goettingen
Germany	Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet	Greifswald
Germany	St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH	Hagen
Germany	Internistische Praxis - Halle	Halle
Germany	Universitaetsklinikum Halle	Halle
Germany	Asklepios Klinik St. Georg	Hamburg
Germany	University Medical Center Hamburg - Eppendorf	Hamburg
Germany	Evangelische Krankenhaus Hamm	Hamm
Germany	St. Marien-Hospital Hamm - Klinik Knappenstrasse	Hamm
Germany	Krankenhaus Siloah - Medizinische Klinik II	Hannover
Germany	Universitatsklinikum Heidelberg	Heidelberg
Germany	Marienhospital at Ruhr University Bochum	Herne
Germany	Privatklinik Dr. R. Schindlbeck GmbH & Co. KG	Herrsching
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Clinic for Bone Marrow Transplantation and Hematology and Oncology	Idar-Oberstein
Germany	Gemeinschaftspraxis Innere Medizin	Jena
Germany	St. Vincentius-Kliniken	Karlsruhe
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Internistische Gemeinschaftspraxis - Kassel	Kassel
Germany	Klinikum Kempten Oberallgaeu	Kempten
Germany	Internistische Praxis - Kiel	Kiel
Germany	University Hospital Schleswig-Holstein - Kiel Campus	Kiel
Germany	Praxis fuer Haematologie und Onkologie	Koblenz
Germany	Stiftungsklinikum Mittelrhein - Gesundheitszentrum Evangelisches Stift Sankt Martin Koblenz gGmbH	Koblez
Germany	Internistische Onkologische Praxis - Kronach	Kronach
Germany	Klinikum Landshut	Landshut
Germany	Onkologische Schwerpunktpraxis - Leer	Leer
Germany	Klinikum "St. Georg" Leipzig	Leipzig
Germany	Klinikum Lippe - Lemgo	Lemgo
Germany	Internistische Praxis - Loerrach	Loerrach
Germany	Gemeinschaftspraxis - Ludwigshafen	Ludwigshafen
Germany	Sana Kliniken Luebeck	Luebeck
Germany	Internistische Gemeinschaftspraxis - Magdeburg	Magdeburg
Germany	Staedtisches Klinikum Magdeburg - Altstadt	Magdeburg
Germany	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg
Germany	Universitatsklinik Mainz	Mainz
Germany	III Medizinische Klinik Mannheim	Mannheim
Germany	Krankenhaus Maria Hilf GmbH	Moenchengladbach
Germany	Hamatologie/Onkologie Praxisgemeinschaft - Muenchen	Muenchen
Germany	Haematologisch - Onkologische Gemeinschaftspraxis	Muenster
Germany	University of Muenster	Muenster
Germany	Haematologische Schwerpunktpraxis	Munich
Germany	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich
Germany	Klinikum Rechts Der Isar - Technische Universitaet Muenchen	Munich
Germany	Staedtisches Krankenhaus Muenchen - Harlaching	Munich
Germany	Onkologische Schwerpunktpraxis Dr. Schmidt	Neunkirchen
Germany	Praxis fuer Haematologie und Interne Onkologie	Norderstedt
Germany	Klinikum Nuernberg - Klinikum Nord	Nuernberg
Germany	Gemeinschaftspraxis - Oberhausen	Oberhausen
Germany	Internistische Gemeinschaftspraxis - Offenbach	Offenbach
Germany	Internistische Gemeinschaftspraxis - Oldenburg	Oldenburg
Germany	Klinikum Oldenburg	Oldenburg
Germany	Asklepios Klinik Pasewalk	Pasewalk
Germany	Municipal Hospital Complex	Pforzheim
Germany	Klinikum Ernst Von Bergmann	Potsdam
Germany	Elisabeth Krankenhaus	Recklinghausen
Germany	Krankenhaus Barmherzige Brueder Regensburg	Regensburg
Germany	Klinik und Poliklinik fuer Innere Medizin - Universitaet Rostock	Rostock
Germany	Caritasklinik St. Theresia	Saarbrucken
Germany	Nordwestkrankenhaus Sanderbusch	Sanderbusch
Germany	St. Marien - Krankenhaus Siegen GMBH	Siegen
Germany	Diakonie Klinikum Stuttgart	Stuttgart
Germany	Haematologische Praxis	Stuttgart
Germany	Internistische Gemeinschaftspraxis - Stuttgart	Stuttgart
Germany	Klinik fuer Onkologie - Katharinenhospital Stuttgart	Stuttgart
Germany	Marienhospital Stuttgart	Stuttgart
Germany	KKH Torgau	Torgau
Germany	Krankenanstalt Mutterhaus der Borromaerinnen	Trier
Germany	Onkologische Gemeinschaftspraxis - Trier	Trier
Germany	Praxis Fuer Internistische Haematologie / Onkologie	Troisdorf
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
Germany	Municipal Hospital Complex	Villingen-Schwenningen
Germany	Praxis fur Innere Medizin - Wanzleben	Wanzleben
Germany	Haematologische Praxis	Weiden
Germany	Schwerpunktpraxis Hamatologie/Onkologie - Wesel	Wesel
Germany	Dr. Horst-Schmidt-Kliniken	Wiesbaden
Germany	Medizinische Klinik und Poliklinik II - Universitaetsklinikum Wuerzburg	Wuerzburg
Germany	Kliniken St. Antonius	Wuppertal 2
Germany	Hamatologisch - Onkologische Praxis Wurzburg	Wurzburg
Israel	Soroka University Medical Center	Beer-Sheva
Israel	BNAI Zion Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Hadassah University Hospital	Jerusalem
Israel	Riverview Cancer Care Medical Associates, PC	Kfar Saba
Israel	Kaplan Hospital	Rehovot
Italy	Ospedale Oncologico A. Businco	Cagliari
Italy	Fondazione Centro San Raffaele Del Monte Tabor	Milano
Italy	Perugia Regional Cancer Center	Perugia
Italy	Ospedale Sant' Eugenio	Rome
Italy	Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore	Rome
New Zealand	Auckland City Hospital	Auckland
New Zealand	Canterbury Health Laboratories	Christchurch
New Zealand	Palmerston North Hospital	Palmerston North
Spain	Hospital General Universitario Morales Meseguer	Murcia
Spain	Hospital Virgen Del La Salud	Toledo

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	German CLL Study Group

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Czech Republic,  Denmark,  France,  Germany,  Israel,  Italy,  New Zealand,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.	Median observation time at time of analysis was approximately 21 months	No
Primary	Final Analysis: Time to Progression-free Survival Event	Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.	Median observation time was approximately 66.4 months	No
Secondary	Event-free Survival (EFS)	Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.	Median observation time at time of analysis was approximately 21 months	No
Secondary	Overall Survival (OS)	Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.	Median observation time at time of analysis was approximately 21 months	No
Secondary	Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.	Median observation time at time of analysis was approximately 21 months	No
Secondary	Final Analysis: Time to Overall Survival Event	Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.	Median observation time was approximately 66.4 months	No
Secondary	Final Analysis: Time to Event-free Survival Event	Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.	Median observation time was approximately 66.4 months	No
Secondary	Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death	Median observation time was approximately 66.4 months	No
Secondary	Final Analysis: Duration of Response	Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.	Median observation time was approximately 66.4 months	No
Secondary	Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.	Median observation time was approximately 66.4 months	No
Secondary	Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)	The time from randomization to the start of a new treatment.	Median observation time was approximately 66.4 months	No

External Links

•   Clinical Study Report Synopsis