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Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)

Primary Purpose

Leukemia

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Rituximab
Sponsored by
University Hospital, Tours
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring B-cell chronic lymphocytic leukemia, Maintenance in first-line treatment, Elderly patients

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

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 2 or more
  • 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
  • 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 and iwCLL criteria at the end of induction phase
  • Recovery from FCR toxicities
  • Patient willingness to continue on protocol

Sites / Locations

  • French Innovative leukemia Organization

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Observation

rituximab arm

Arm Description

Observation every 8 weeks during 2 years

rituximab :500 mg/m² every 8 weeks during 2 years

Outcomes

Primary Outcome Measures

Progression-free survival
Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria

Secondary Outcome Measures

Event-free survival
Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
Disease-free survival
Disease-free survival is defined as the time from first documented CR to relapse
Overall survival
Overall survival is defined as the time from randomization to death from any cause
Time to next treatment
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
Overall response rate
Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
Phenotypic response rate
Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
Rates of treatment-related adverse events
Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
Pharmacokinetics of rituximab
Pharmacokinetics of rituximab during induction and rituximab maintenance
Quality of life
Change from baseline in EORTC Quality of Life Questionnaire Core 30

Full Information

First Posted
March 26, 2008
Last Updated
July 27, 2017
Sponsor
University Hospital, Tours
Collaborators
Roche Pharma AG, French Innovative Leukemia Organisation
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1. Study Identification

Unique Protocol Identification Number
NCT00645606
Brief Title
Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia
Acronym
LLC2007SA
Official Title
Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab in Patients Older Than 65 Years With Previously Untreated Chronic Lymphocytic Leukemia: a Phase III Trial of FILO
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
July 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Tours
Collaborators
Roche Pharma AG, French Innovative Leukemia Organisation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Classical chemotherapy does not cure advanced chronic lymphocytic leukemia (CLL) despite new drugs. Rituximab is a monoclonal antibody directed against CD20 surface antigen on B lymphocytes and leads to apoptosis of CD20 positive B lymphocytes. The highest response rate yet published in the treatment of first-line CLL has been obtained by the association of fludarabine, cyclophosphamide and rituximab (FCR). Now, the question is whether this response can be improved, as some trials showed that eradication of minimal residual disease (MRD) in CLL is associated with a longer treatment-free and overall survival. Maintenance therapy using rituximab has been recently approved as a means of prolonging remission in patients with indolent non Hodgkin's lymphoma. Maintenance therapy with rituximab could be of interest in treatment of MRD in CLL and prolonging remission and survival times. PURPOSE: The overall purpose of the study is to determine the value of immunotherapy maintenance with single agent rituximab in comparison with no further treatment (observation ) for previously untreated chronic lymphocytic leukaemia in elderly (>65 years) patients who respond to induction immunochemotherapy with FCR.
Detailed Description
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, 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 and iwCLL criteria To assess the rate of phenotypic response (minimal residual disease). To assess duration of phenotypic and NCI and iwCLL clinical responses. To determine response rates and time-related parameters in biological subgroups. To determine rates of treatment-related adverse events. To evaluate 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. Randomization is stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IGHV 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 and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses are administered every 28 days. Patients achieving CR or PR are randomized 1:1 to maintenance arm or observation arm. Arm A: Patients receive rituximab IV every 2 months in the absence of disease progression or unacceptable toxicity for a maximum duration of 24 months (12 infusions). Arm B: Patients undergo observation only. After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
B-cell chronic lymphocytic leukemia, Maintenance in first-line treatment, Elderly patients

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
542 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Observation
Arm Type
No Intervention
Arm Description
Observation every 8 weeks during 2 years
Arm Title
rituximab arm
Arm Type
Experimental
Arm Description
rituximab :500 mg/m² every 8 weeks during 2 years
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
rituximab :500 mg/m² every 8 weeks during 2 years
Primary Outcome Measure Information:
Title
Progression-free survival
Description
Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria
Time Frame
randomization until disease progression or death
Secondary Outcome Measure Information:
Title
Event-free survival
Description
Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
Time Frame
randomization until disease progression, death, new CLL treatment, and secondary cancer
Title
Disease-free survival
Description
Disease-free survival is defined as the time from first documented CR to relapse
Time Frame
first documented CR until relapse
Title
Overall survival
Description
Overall survival is defined as the time from randomization to death from any cause
Time Frame
randomization until death
Title
Time to next treatment
Description
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
Time Frame
randomization until new CLL treatment
Title
Overall response rate
Description
Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
Time Frame
baseline up to approximately 66 months
Title
Phenotypic response rate
Description
Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
Time Frame
randomization up to approximately 60 months
Title
Rates of treatment-related adverse events
Description
Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
Time Frame
safety since baseline
Title
Pharmacokinetics of rituximab
Description
Pharmacokinetics of rituximab during induction and rituximab maintenance
Time Frame
baseline up to approximately 36 months
Title
Quality of life
Description
Change from baseline in EORTC Quality of Life Questionnaire Core 30
Time Frame
baseline up to approximately 30 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 2 or more 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 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 and iwCLL criteria at the end of induction phase Recovery from FCR toxicities Patient willingness to continue on protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Caroline Dartigeas, MD
Organizational Affiliation
Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Eric VAN DEN NESTE, MD PhD
Organizational Affiliation
Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM
Official's Role
Principal Investigator
Facility Information:
Facility Name
French Innovative leukemia Organization
City
TOURS Cedex
ZIP/Postal Code
37044
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
29275118
Citation
Dartigeas C, Van Den Neste E, Leger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Lepretre S, Bene MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahe B, Laribi K, Michallet AS, Delmer A, Feugier P, Levy V, Delepine R, Colombat P, Leblond V; CLL 2007 SA investigators; French Innovative Leukemia Organization (FILO). Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. doi: 10.1016/S2352-3026(17)30235-1. Epub 2017 Dec 20.
Results Reference
derived

Learn more about this trial

Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia

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