LeukemiaPhase 3LLC2007SANCT00645606
Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia
A Phase 3 study testing Rituximab in people with Leukemia, run by University Hospital, Tours at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 65 years and older
- Conditions the study is for
- Leukemia
- What is being tested?
- Rituximab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 542 participants
- Where
- 1 siteFrance
- Study dates
- Dec 2007to Jul 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 years and older
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- 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
Show all 11Show fewer
- Life expectancy > 6 months
- 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
Who cannot join
- 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)
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabBiological
Also called Mabthera
rituximab :500 mg/m² every 8 weeks during 2 years
| Study group | Role | What they receive |
|---|---|---|
| Observation | No intervention | Observation every 8 weeks during 2 years |
| rituximab arm | Experimental | rituximab :500 mg/m² every 8 weeks during 2 years Receives: Biological: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: randomization until disease progression or death
Secondary outcomes (9)
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
Measured: 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
Measured: first documented CR until relapse
Overall survival
Overall survival is defined as the time from randomization to death from any cause
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: safety since baseline
Pharmacokinetics of rituximab
Pharmacokinetics of rituximab during induction and rituximab maintenance
Measured: baseline up to approximately 36 months
Quality of life
Change from baseline in EORTC Quality of Life Questionnaire Core 30
Measured: baseline up to approximately 30 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2008 (estimated)
- Study startDec 2007
- Primary completionFeb 2014
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by University Hospital, ToursThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 542 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Tours
- Sponsor type
- University, hospital or other
- Collaborators
- Roche Pharma AG, French Innovative Leukemia Organisation
- Responsible party
- Sponsor
- Investigators
- Caroline Dartigeas, MD, Principal investigator, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCEEric VAN DEN NESTE, MD PhD, Principal investigator, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00645606
- Sponsor's protocol ID
- CDR0000589684
- Other IDs
- CHRUT-LLC-2007-SA, CHRUT-PHRN05-CD, INCA-RECF0497, 2007-001015-28
- Acronym
- LLC2007SA
- Status last verified
- Jul 2017
- First submitted
- 26 Mar 2008
- Last updated
- 1 Aug 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 29275118
Study at a glance
From the registry record, last updated by the sponsor on 1 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00645606
- Acronym / sponsor ID
- LLC2007SA / CDR0000589684
- Conditions
- Leukemia
- Keywords
- B-cell chronic lymphocytic leukemia, Maintenance in first-line treatment, Elderly patients
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 542 participants (actual)
- Lead sponsor
- University Hospital, ToursUniversity, hospital or other
- Collaborators
- Roche Pharma AG, French Innovative Leukemia Organisation
- Study start
- Dec 2007
- Primary completion
- Feb 2014 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 27 Mar 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Observation | No intervention | –Observation every 8 weeks during 2 years |
| rituximab arm | Experimental | Biological: Rituximabrituximab :500 mg/m² every 8 weeks during 2 years |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: Mabtherarituximab :500 mg/m² every 8 weeks during 2 years | Biological | rituximab arm |
Primary outcome
Progression-free survival
Time frame: randomization until disease progression or death
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
9 secondary outcomes
Event-free survival
Time frame: randomization until disease progression, death, new CLL treatment, and secondary cancer
Disease-free survival
Time frame: first documented CR until relapse
Overall survival
Time frame: randomization until death
Time to next treatment
Time frame: randomization until new CLL treatment
Overall response rate
Time frame: baseline up to approximately 66 months
Phenotypic response rate
Time frame: randomization up to approximately 60 months
Rates of treatment-related adverse events
Time frame: safety since baseline
Pharmacokinetics of rituximab
Time frame: baseline up to approximately 36 months
Quality of life
Time frame: baseline up to approximately 30 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Aug 2017.
- Derived from this study: PubMed 29275118Dartigeas 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.
- Individual participant dataSharing planned: No
Related trials for Leukemia
RecruitingPhase 2
Tafasitamab With Acalabrutinib and Venetoclax for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Study of CHM-029 in Participants With NPM1 Mutated, KMT2A or NUP98 Rearranged AML
AML (Acute Myeloid Leukemia)
RecruitingPhase 1
Vididencel in CML-CP Patients With MRD
CML (Chronic Myelogenous Leukemia)
RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Caroline Dartigeas, MD principal investigator
Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
Eric VAN DEN NESTE, MD PhD principal investigator
Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rituximab in people with Leukemia, run by University Hospital, Tours at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression-free survival (time frame: randomization until disease progression or death). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00645606, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2017.