Fludarabine, Cyclophosphamide, and Rituximab Followed by Rituximab or Observation in Treating Older Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia (LLC2007SA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University Hospital, Tours
Sponsor:
Collaborators:
FCGCLL-WM
Roche Pharma AG
Information provided by (Responsible Party):
University Hospital, Tours
ClinicalTrials.gov Identifier:
NCT00645606
First received: March 26, 2008
Last updated: September 15, 2014
Last verified: September 2014

March 26, 2008
September 15, 2014
December 2007
September 2017   (final data collection date for primary outcome measure)
Three-year progression-free survival [ Time Frame: from randomisation to progression or relapse ] [ Designated as safety issue: Yes ]
induction treatment + at 36 months from randomisation
Three-year progression-free survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00645606 on ClinicalTrials.gov Archive Site
  • Event-free survival [ Time Frame: from randomisation to first event ] [ Designated as safety issue: Yes ]
  • Disease-free survival [ Time Frame: from first documented CR to relapse ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: From randomisation to death from any cause ] [ Designated as safety issue: Yes ]
  • Time to next treatment [ Time Frame: From randomisation to initiation of a new disease-related treatment ] [ Designated as safety issue: Yes ]
  • Overall response rate, complete response, and partial response according to NCI criteria [ Time Frame: response post induction and response at 36 months from randomisation ] [ Designated as safety issue: Yes ]
  • Rates of phenotypic response (minimal residual disease) [ Time Frame: response post induction and response at 36 months from randomisation ] [ Designated as safety issue: Yes ]
  • Rates of treatment-related adverse events [ Time Frame: all over the study duration ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics of rituximab during induction and maintenance [ Time Frame: during induction and maintenance treatment ] [ Designated as safety issue: Yes ]
  • Quality of life [ Time Frame: post induction and during maintenance phase ] [ Designated as safety issue: Yes ]
  • Event-free survival [ Designated as safety issue: Yes ]
  • Disease-free survival [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Time to next treatment [ Designated as safety issue: No ]
  • Overall response rate, complete response, and partial response according to NCI criteria [ Designated as safety issue: No ]
  • Rates of phenotypic response (minimal residual disease) [ Designated as safety issue: No ]
  • Duration of phenotypic and NCI clinical responses [ Designated as safety issue: No ]
  • Response rates and time-related parameters in biological subgroups [ Designated as safety issue: No ]
  • Rates of treatment-related adverse events [ Designated as safety issue: Yes ]
  • CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia [ Designated as safety issue: No ]
  • Pharmacokinetics of rituximab during induction and maintenance [ Designated as safety issue: No ]
  • Prognostic impact of the immunoglobulin FcγRIIIA genotype [ Designated as safety issue: No ]
  • Quality of life [ Designated as safety issue: No ]
  • Pharmacoeconomics [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Fludarabine, Cyclophosphamide, and Rituximab Followed by Rituximab or Observation in Treating Older Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia
Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients Older Than 65 Years With Previously Untreated B-cell Chronic Lymphocytic Leukemia (B-CLL): a Phase III Intergroup Trial of the GOELAMS and the FCGCLL/WM Groups

RATIONALE: 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. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving rituximab alone after chemotherapy and rituximab is more effective than chemotherapy and rituximab followed by observation in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying giving fludarabine together with cyclophosphamide and rituximab followed by rituximab alone to see how well it works compared with giving fludarabine together with cyclophosphamide and rituximab followed by observation in treating older patients with previously untreated B-cell chronic lymphocytic leukemia.

OBJECTIVES:

Primary

  • To demonstrate superiority, in terms of 3-year progression-free survival (PFS), of rituximab maintenance over observation in patients who are in complete or partial response (CR or PR) after induction therapy comprising fludarabine phosphate, cyclophosphamide, and rituximab.

Secondary

  • To determine event-free survival, disease-free survival, overall survival, and time to next treatment, all from time of randomization.
  • To determine overall response rate (CR and PR) according to NCI criteria.
  • To assess the rate of phenotypic response (minimal residual disease).
  • To assess duration of phenotypic and NCI clinical responses.
  • To determine response rates and time-related parameters in biological subgroups.
  • To determine rates of treatment-related adverse events.
  • To evaluate of CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia.
  • To study pharmacokinetics of rituximab during induction and maintenance.
  • To evaluate the prognostic impact of the immunoglobulin FcγRIIIA genotype.
  • To assess quality of life.
  • To study pharmacoeconomics.

OUTLINE: This is a multicenter study. Patients are stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IgV_H mutational status, and 11q deletion.

Patients receive rituximab IV on days 1 and 14 of courses 1-2 and on day 1 of courses 3 and 4. Patients also receive oral fludarabine phosphate and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses repeat every 28 days. Patients achieving CR or PR are randomized to 1 of 2 maintenance arms once they have recovered from toxicities.

  • Arm A: Patients receive rituximab IV on day 1. Treatment repeats every 2 months in the absence of disease progression for a maximum duration of 24 months (12 infusions).
  • Arm B: Patients undergo observation only. Patients undergo lymphocyte sample collection for biological studies including diagnostic immunophenotyping, Matutes score (with CD38, CD20, and CD43) , ZAP-70 analysis, standard karyotyping, cytogenetic screening by FISH (17p13 deletion, 11q22 deletion, 13q14 deletion, and trisomy 12), IgV_H mutational status, serum thymidine kinase, FcγRIIIA genotyping, and pharmacokinetic study. Samples are frozen and stored for later studies.

After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for up to 4 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Leukemia
Biological: Rituximab
rituximab :500 mg/m² every 8 weeks every 2 years
Other Name: Mabthera
  • No Intervention: Observation
    Observation every 8 months during 2 years
  • Experimental: rituximab arm
    rituximab :500 mg/m² every 8 weeks every 2 years
    Intervention: Biological: Rituximab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
542
August 2019
September 2017   (final data collection date for primary outcome measure)

Inclusion criteria

  • B-CLL
  • Matutes score 4 or 5
  • Binet stages B or C
  • Age > 65 years old
  • No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy, except glucocorticoids < 1 month
  • Patient's written informed consent
  • Life expectancy > 6 months

Exclusion criteria

  • Binet stage A
  • ECOG performance status 0 or 1
  • Presence of a 17p deletion by FISH (> 10% positive cores)
  • Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
  • Patients with a history of another malignancy in complete remission less than 5 years, except basal cell skin cancer or tumor treated curatively by surgery
  • Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
  • Any severe co-morbidities such as NYHA Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia, or uncontrolled diabetes mellitus.
  • CIRS (Cumulative Illness rating Scale) > 6 (see Appendix 11)
  • Known hypersensitivity to murine proteins or to any of the study drugs or to their components
  • Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma) or prolymphocytic leukemia
  • Active bacterial, viral or fungal infection
  • Seropositivity HIV, hepatitis C or hepatitis B (unless clearly due to vaccination)
  • Total bilirubin, alkaline phosphatases and aminotransferases > 2 x ULN
  • Creatinine clearance < 60 ml/min calculated according to the formula of Cockcroft and Gault
  • Any coexisting medical or psychological condition that would preclude participation to the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment

Inclusion criteria at randomization

  • Patients having received the full induction phase with 4 FC and 6 rituximab courses (with/without dose adjustments as per protocol)
  • Complete or partial response according to NCI criteria at the end of induction phase
  • Recovery from FCR toxicities
  • Patient willingness to continue on protocol
Both
66 Years and older
No
Contact: Caroline DARTIGEAS, MD +33247473712 c.dartigeas@chu-tours.fr
Contact: Roselyne DELEPINE, Mrs +33047473798 r.delepine@chu-tours.fr
France
 
NCT00645606
CDR0000589684, CHRUT-LLC-2007-SA, CHRUT-PHRN05-CD, INCA-RECF0497, EUDRACT-2007-001015-28
Yes
University Hospital, Tours
University Hospital, Tours
  • FCGCLL-WM
  • Roche Pharma AG
Principal Investigator: Caroline Dartigeas, MD Centre Hospitalier Universitaire Bretonneau de Tours
Principal Investigator: Eric VAN DEN NESTE, MD PhD FCGCLL/MW
University Hospital, Tours
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP