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

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

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.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Biological: Rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 542
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • TOURS Cedex, France, 37044
    • French Innovative Leukemia Organization

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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
No Intervention: Observation; Observation every 8 weeks during 2 years
Experimental: rituximab arm; rituximab :500 mg/m² every 8 weeks during 2 years	Biological: Rituximab; rituximab :500 mg/m² every 8 weeks during 2 years; Other Names: Mabthera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	randomization until disease progression or death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	randomization until disease progression, death, new CLL treatment, and secondary cancer
Disease-free survival	Disease-free survival is defined as the time from first documented CR to relapse	first documented CR until relapse
Overall survival	Overall survival is defined as the time from randomization to death from any cause	randomization until death
Time to next treatment	Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment	randomization until new CLL 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	baseline up to approximately 66 months
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	randomization up to approximately 60 months
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	safety since baseline
Pharmacokinetics of rituximab	Pharmacokinetics of rituximab during induction and rituximab maintenance	baseline up to approximately 36 months
Quality of life	Change from baseline in EORTC Quality of Life Questionnaire Core 30	baseline up to approximately 30 months

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: Roche Pharma AG; French Innovative Leukemia Organisation
• Investigators: Principal Investigator: Caroline Dartigeas, MD, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE; Principal Investigator: Eric VAN DEN NESTE, MD PhD, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: March 26, 2008
• First Submitted That Met QC Criteria: March 26, 2008
• First Posted (Estimate): March 27, 2008

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 27, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: B-cell chronic lymphocytic leukemia; Elderly patients; Maintenance in first-line treatment
• 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; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: CDR0000589684; CHRUT-LLC-2007-SA (Other Identifier: CHU Tours); CHRUT-PHRN05-CD (Other Identifier: CHU Tours); INCA-RECF0497 (Other Identifier: INCA); 2007-001015-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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