FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients

Open-label, Multicenter, Randomized, Comparative, Phase III Study to Evaluate the Efficacy and Safety of FCR vs. FC Alone in Previously Treated Patients With CD20 Positive B-cell CLL

The purpose of this study is to provide treatment for patients who have chronic lymphocytic leukemia (CLL), and to compare the use of rituximab added to fludarabine+cyclophosphamide (FC) with FC alone, to determine if rituximab lengthens the time a patient remains free of leukemia symptoms.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Rituximab; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate

• Study Type: Interventional
• Enrollment (Actual): 552
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital; Haematology
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Mater Hospital; Division of Cancer Services
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital; Oncology/Haematology
    • Melbourne, Victoria, Australia, 3000
      • Peter Maccallum Cancer Institute; Medical Oncology
• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R7
      • Uni of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA-Vancouver Cancer Centre
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Health Science Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • QEII HSC; Oncology
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Hamilton Health Sciences - Juravinski Cancer Centre; Hematology
    • Ottawa, Ontario, Canada, K1H 1C4
      • The Ottawa Regional Hospital - General Campus; Division of Hematology, Box 704
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network; Princess Margaret Hospital; Medical Oncology Dept
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
      • Mcgill University - Royal Victoria Hospital; Oncology
• Denmark
  • København Ø, Denmark, 2100
    • Righospitalet, Hæmatologisk Klinik
  • Århus, Denmark, 8000
    • Aarhus Universitetshospital, Hæmatologisk Afdeling R
• France
  • Bobigny, France, 93009
    • Hopital Avicenne; Hematologie Biologique
  • Caen, France, 14033
    • Hopital Clemenceau; Hematologie Clinique
  • Clermont Ferrand, France, 63003
    • Chu Estaing; Hematologie Clinique Adultes
  • Creteil, France, 94010
    • Hopital Henri Mondor; Hematologie Clinique
  • Le Mans, France, 72015
    • Clinique Victor Hugo; Chimiotherapie
  • Lille, France, 59037
    • Hopital Claude Huriez; Hematologie
  • Lyon, France, 69373
    • Centre Leon Berard; Departement Oncologie Medicale
  • Lyon, France, 69003
    • Hopital Edouard Herriot; Bat.E-Hematologie
  • Marseille, France, 13273
    • Institut J Paolii Calmettes; Onco Hematologie 1
  • Montpellier, France, 34295
    • Hôpital Lapeyronie; Hématologie Oncologie Médicale
  • Nantes, France, 44093
    • Hopital Hotel Dieu Et Hme;Hopital De Jour
  • Paris, France, 75181
    • Hotel Dieu; Hematologie- Oncologie
  • Paris, France, 75651
    • Hopital Pitie Salpetriere; Hematologie Clinique
  • Paris, France, 75475
    • Inserm Cic 9504
  • Pierre Benite, France, 69495
    • Ch Lyon Sud; Hemato Secteur Jules Courmont
  • Poitiers, France, 86021
    • Chu La Miletrie; Hdj Cons Hemato Cancerologie
  • Rouen, France, 76038
    • Centre Henri Becquerel; Hematologie
  • Tours, France, 37044
    • Hopital Bretonneau; Clinique D'Oncologie & de Radiotherapie
  • Vandoeuvre Les Nancy, France, 54511
    • Hopitaux De Brabois; Hematologie Medecine Interne
• Hungary
  • Budapest, Hungary, 1122
    • National Institute of Oncology, A Dept of Internal Medicine
  • Budapest, Hungary, 1097
    • Szent Laszlo Hospital; Hematology Dept
  • Budapest, Hungary, 1135
    • Országos Gyógyintézeti Központ; Haematologiai Osztaly
  • Debrecen, Hungary, 4032
    • University of Debrecen Medical and Health Science Center, Institute of Internal Medicine, Hematology
  • Debrecen, Hungary, 4004
    • Uni of Debrecen; 2Nd Clinic of Internal Medicine
  • Pecs, Hungary, 7624
    • Uni of Pecs; Dept of Internal Medicine
  • Szeged, Hungary, 6720
    • University of Szeged, II Dept of Internal Medicine
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • A.O. Universitaria Federico II Di Napoli; Oncologia Ed Endocrinologia Clinica
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna
  • Lazio
    • Roma, Lazio, Italy, 00161
      • Universita' Degli Studi La Sapienza-Ist.Di Ematologia;Dip. Biotecnologie Cel CELLULARI ED EMATOLOGIA
    • Roma, Lazio, Italy, 00144
      • Ospedale S. Eugenio; Divisione Di Ematologia
    • Roma, Lazio, Italy, 00152
      • Az. Osp. S. Camillo Forlanini; Uo Ematologia E Trapianti Di Midollo Osseo
  • Lombardia
    • Milano, Lombardia, Italy, 20162
      • Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
    • Pavia, Lombardia, Italy, 27100
      • Irccs Policlinico San Matteo; Divisione Di Ematologia
  • Puglia
    • Bari, Puglia, Italy, 70124
      • Uni Degli Studi Di Bari, Policlinico; Cattedra Di Ematologia,Dipart. Di Medicina Interna E Publica
    • San Giovanni Rotondo, Puglia, Italy, 71013
      • IRCCS Ospedale Casa Sollievo Della Sofferenza; Ematologia E Trapianto Di Midollo Osseo
  • Veneto
    • Vicenza, Veneto, Italy, 36100
      • Ospedale Di Vicenza; Nefrologia, Ematologia
• Netherlands
  • Amersfoort, Netherlands, 3818 ES
    • Meander Mc, Locatie Lichtenberg; Dept of Lung Diseases
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum Universiteit Amsterdam
  • Den Haag, Netherlands, 2545 CG
    • Leyenburg Ziekenhuis; Haematology
  • Rotterdam, Netherlands, 3075 EA
    • Erasmus Mc - Daniel Den Hoed Kliniek; Medical Oncology
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland city hospital; Auckland Regional Cancer Centre and Blood Service
  • Christchurch, New Zealand
    • Christchurch Hospital; Canterbury Health Laboratories
  • Wellington, New Zealand, 6002
    • Wellington Hospital; Regional Oncology Unit
• Norway
  • Bergen, Norway, 5021
    • Haukeland Universitetshospital; Medicine Dept
  • Oslo, Norway, 0027
    • Rikshospitalet Uni Hospital
• Poland
  • Lodz, Poland, 93-510
    • Medical University School; Dept. of Haematology
  • Lublin, Poland, 20-081
    • Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie
  • Poznan, Poland, 02-097
    • Akademii Medycznej W; Klinika Hematologii
  • Warszawa, Poland, 00-909
    • Klin. Chorob Wewnetrznych I Hemat. Z Osrodkiem Transplant. Szpiku
  • Warszawa, Poland, 00-957
    • Instytut Hematologii I Transfuzjologii; Klinika Chorob Wewnetrznych I Hematologii
  • Warszawa, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczny; Haematology Dept.
• Romania
  • Bucharest, Romania, 022328
    • Fundeni Clinical Inst. ; Hematology Dept
  • Bucuresti, Romania, 030171
    • Spitalul Clinic Coltea; Clinica de Hematologie
  • Targu-mures, Romania, 540136
    • Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie
  • Timisoara, Romania, 300079
    • Spitalul Clinic municipal de Urgenta Timisoara; Clinica de Hematologie
• Russian Federation
  • Moscow, Russian Federation, 115478
    • N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis
  • Moscow, Russian Federation, 125167
    • Haematology Research Center; Haematology
  • Moscow, Russian Federation, 125284
    • City Clinical Botkin's Hospital; City Hematological Center
  • Obninsk, Russian Federation, 249036
    • Medical Radiological Research Centre Rams; Dept. of Radiotherapy & Chemotherapy of Hemoblastosis
  • Samara, Russian Federation, 443095
    • Regional Clinical Hospital N.A. Kalinin; Hematology Dept
  • St Petersburg, Russian Federation, 197022
    • Pavlov State Medical Uni ; Bone Marrow Transplantation Clinic
  • St Petersburg, Russian Federation, 197022
    • S.-Peterburg Pavlov State Medical University ; Haematology
  • St Petersburg, Russian Federation, 193024
    • Research Inst. Hematology /Blood Transfusion ; Hemablastosis, Supression Hemopoesis & B M Transplant
  • St Petersburg, Russian Federation, 194291
    • Regional Clinical Hospital; Hematology Dept. #2 For B M Transplantation & High Dose Chemo.
  • St Petersburg, Russian Federation, 197110
    • State Medical Inst. Municipal Hospital #31; Oncology & Hematology Dept. With the Usechemo. in Adult
• Spain
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa; Servicio de Hematologia
  • Madrid, Spain, 28041
    • Hospital Univ. 12 de Octubre; Servicio de Hematologia
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet; Servicio Hematologia
• Sweden
  • Huddinge, Sweden, 14186
    • Karolinska Inst. , Huddinge Uni Hospital; Depart. of Hematology
  • Linkoeping, Sweden, 581 85
    • Universitetssjukhuset i Linköping, Hematologkliniken
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth General Hospital; Haematology
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital; Haematology
  • Glasgow, United Kingdom, G83 8NG
    • Stobhill Hospital; Dept of Haematology
  • Leeds, United Kingdom, LS1 3EX
    • Leeds General Infirmary; Medicine
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary; Dept of Haematology
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool Uni Hospital; Haematology
  • London, United Kingdom, EC1A 7BE
    • St. Bartholomew'S Hospital; Dept of Medical Oncology
  • London, United Kingdom, SE5 9RS
    • King'S College Hospital; Haematology
  • Sutton, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital; Academic Dept of Haematology
  • Wakefield, United Kingdom, WF1 4DG
    • Pinderfields General Hospital; Dept of Haematology
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • Uab Comprehensive Cancer Center
  • California
    • Fountain Valley, California, United States, 92708
      • Pacific Coast Hematology/Oncology Medical Group
    • Fresno, California, United States, 93720
      • California Cancer Center Woodward Park; Community Medical Centers
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush-Presbyterian St. Luke's Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Milton S. Hershey Medical Center; Penn State Cancer Inst.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 years
• Established diagnosis of B-cell CLL by NCI Working Group criteria
• ≤1 previous line of chemotherapy
• Expected survival >6 months
• Acceptable hematologic status, liver function, renal function, and pulmonary function
• Negative serum pregnancy test for both pre-menopausal women and for women who are < 2 years after the onset of menopause
• Written informed consent

Exclusion Criteria:

• Prior treatment with interferon, rituximab or other monoclonal antibody
• Prior allogeneic bone marrow transplant (BMT) or autologous BMT or peripheral stem cell transplant (PBSCT) or patients who are considered to be candidates for allogeneic or autologous BMT or PSCT as assessed by their treating physician
• Fertile men or women of childbearing potential not using adequate contraception
• Severe Grade 3 or 4 non-hematological toxicity or prolonged (> 2 weeks) Grade 3 or 4 cytopenia on prior fludarabine or nucleoside analogue regimen
• History of fludarabine-induced or clinically significant autoimmune cytopenia
• History of other malignancies within 2 years prior to study entry, except for adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low-grade early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent.
• Medical conditions requiring long term use (> 1 month) of systemic corticosteroids
• Active bacterial, viral, or fungal infection requiring systemic therapy
• Severe cardiac disease
• Seizure disorders requiring anticonvulsant therapy
• Severe chronic obstructive pulmonary disease with hypoxemia
• Uncontrolled diabetes mellitus or hypertension
• Transformation to aggressive B-cell malignancy.
• Known infection with HIV, HCV, or hepatitis B
• Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study
• Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins
• Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fludarabine+Cyclophosphamide+Rituximab (FCR)	Drug: Rituximab; Intravenous repeating dose; Drug: Cyclophosphamide; Intravenous repeating dose; Drug: Fludarabine Phosphate; Intravenous repeating dose
Active Comparator: Fludarabine+Cyclophosphamide (FC)	Drug: Cyclophosphamide; Intravenous repeating dose; Drug: Fludarabine Phosphate; Intravenous repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC)	Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause, whichever came first. Patients without a PFS event were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC)	Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause (PFS events), whichever came first. Patients without a PFS event were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Final Analysis: Time to Progression-Free Survival Event	Time to progression-free survival (PFS) event was defined as the time between randomization and the date of first documented PFS event: disease progression, relapse or death by any cause, whichever came first.	Median observation time was approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival was determined from the date of randomization to the date of death irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.	Mean observation time at time of analysis was approximately 26 months
Number of Participants With Overall Survival (OS) Events	Overall survival was determined from the date of randomization to the date of death (OS event) irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.	Mean observation time at time of analysis was approximately 26 months
Event-free Survival (EFS)	Event free survival was measured from the day of randomization to the date of first documented PD, relapse after response, start of a new treatment or death from any cause. Patients without an EFS event were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Number of Participants With Event-free Survival (EFS) Events	Event free survival was measured from the day of randomization to the date of first documented Progressive Disease (PD), relapse after response, start of a new treatment or death from any cause (EFS events). Patients without an EFS event were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Disease-free Survival (DFS)	Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause. Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Number of Participants With Disease-free Survival (DFS) Events	Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause (DFS events). Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.	Mean observation time at time of analysis was approximately 26 months
Final Analysis: Time to Overall Survival Event	Overall survival (OS) was determined from the date of randomization to the date of death (OS event) irrespective of cause.	Median observation time was approximately 5 years
Final Analysis: Time to Event-Free Survival Event	Event free survival (EFS) was defined as the time from the day of randomization to the date of first EFS event: documented disease progression, relapse after response, start of a new treatment or death from any cause.	Median observation time was approximately 5 years
Final Analysis: Percentage of Participants With Complete Response	Complete response was defined as the disappearance of all signs of cancer in response to treatment.	Median observation time was approximately 5 years
Final Analysis: Time to Disease-Free Survival Event	Time to disease-free survival (DFS) event was defined as the time from first documented response until the first documented DFS event: disease progression, relapse or death from any cause.	Median observation time was approximately 5 years
Final Analysis: Duration of Response	Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause.	Median observation time was approximately 5 years
Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment	Time to new CCL treatment was defined as the time from randomization to the first day of new treatment for CCL or death.	Median observation time was approximately 5 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Genentech, Inc.; Biogen

Publications and helpful links

General Publications

• Weisser M, Yeh RF, Duchateau-Nguyen G, Palermo G, Nguyen TQ, Shi X, Stinson SY, Yu N, Dufour A, Robak T, Salogub GN, Dmoszynska A, Solal-Celigny P, Warzocha K, Loscertales J, Catalano J, Larratt L, Rossiev VA, Bence-Bruckler I, Geisler CH, Montillo M, Fischer K, Fink AM, Hallek M, Bloehdorn J, Busch R, Benner A, Dohner H, Valente N, Wenger MK, Stilgenbauer S, Dornan D. PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia. Blood. 2014 Jul 17;124(3):420-5. doi: 10.1182/blood-2013-12-538975. Epub 2014 Jun 10.
• Dufour A, Palermo G, Zellmeier E, Mellert G, Duchateau-Nguyen G, Schneider S, Benthaus T, Kakadia PM, Spiekermann K, Hiddemann W, Braess J, Truong S, Patten N, Wu L, Lohmann S, Dornan D, GuhaThakurta D, Yeh RF, Salogub G, Solal-Celigny P, Dmoszynska A, Robak T, Montillo M, Catalano J, Geisler CH, Weisser M, Bohlander SK. Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients. Blood. 2013 May 2;121(18):3650-7. doi: 10.1182/blood-2012-10-458695. Epub 2013 Mar 22.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2003
• Primary Completion (Actual): July 23, 2008
• Study Completion (Actual): May 31, 2012

Study Registration Dates

• First Submitted: August 23, 2004
• First Submitted That Met QC Criteria: August 24, 2004
• First Posted (Estimate): August 25, 2004

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 5, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: 102-14; BO17072