Chronic Lymphocytic Leukemia
Conditions
Brief summary
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.
Interventions
DRUGRituximab
Intravenous repeating dose
DRUGFludarabine Phosphate
Intravenous repeating dose
DRUGCyclophosphamide
Intravenous repeating dose
Sponsors
Biogen
Genentech, Inc.
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | Mean observation time at time of analysis was approximately 26 months | 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. |
| Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Mean observation time at time of analysis was approximately 26 months | 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. |
| Final Analysis: Time to Progression-Free Survival Event | Median observation time was approximately 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Event-free Survival (EFS) Events | Mean observation time at time of analysis was approximately 26 months | 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. |
| Disease-free Survival (DFS) | Mean observation time at time of analysis was approximately 26 months | 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. |
| Number of Participants With Disease-free Survival (DFS) Events | Mean observation time at time of analysis was approximately 26 months | 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. |
| Final Analysis: Time to Overall Survival Event | Median observation time was approximately 5 years | Overall survival (OS) was determined from the date of randomization to the date of death (OS event) irrespective of cause. |
| Overall Survival (OS) | Mean observation time at time of analysis was approximately 26 months | 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. |
| Final Analysis: Percentage of Participants With Complete Response | Median observation time was approximately 5 years | Complete response was defined as the disappearance of all signs of cancer in response to treatment. |
| Final Analysis: Time to Disease-Free Survival Event | Median observation time was approximately 5 years | 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. |
| Final Analysis: Duration of Response | Median observation time was approximately 5 years | 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. |
| Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment | Median observation time was approximately 5 years | Time to new CCL treatment was defined as the time from randomization to the first day of new treatment for CCL or death. |
| Final Analysis: Time to Event-Free Survival Event | Median observation time was approximately 5 years | 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. |
| Number of Participants With Overall Survival (OS) Events | Mean observation time at time of analysis was approximately 26 months | 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. |
| Event-free Survival (EFS) | Mean observation time at time of analysis was approximately 26 months | 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. |
Countries
Australia, Belgium, Canada, Denmark, France, Hungary, Italy, Netherlands, New Zealand, Norway, Poland, Romania, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles. | 276 |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3. | 276 |
| Total | 552 |
Baseline characteristics
| Characteristic | Fludarabine+Cyclophosphamide (FC) | Fludarabine+Cyclophosphamide+Rituximab (FCR) | Total |
|---|---|---|---|
| Age, Continuous | 61.3 Years STANDARD_DEVIATION 9.11 | 62.1 Years STANDARD_DEVIATION 9.17 | 61.7 Years STANDARD_DEVIATION 9.14 |
| Sex: Female, Male Female | 95 Participants | 89 Participants | 184 Participants |
| Sex: Female, Male Male | 181 Participants | 187 Participants | 368 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 232 / 272 | 251 / 274 |
| serious Total, serious adverse events | 132 / 272 | 138 / 274 |
Outcome results
Primary
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.
Time frame: Median observation time was approximately 5 years
Population: Participants from the Intent-to-treat population, all randomized participants, who experienced a PFS event. Participants who did not have a PFS event at the time of the final analysis were censored at the date of the last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Progression-Free Survival Event | 683.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Progression-Free Survival Event | 969.0 Days |
p-value: <0.000195% CI: [0.54, 0.8]Log Rank
Primary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Patients with event | 148 participants |
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Patients without events | 128 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Patients with event | 137 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Patients without events | 139 participants |
Primary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | 660 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | 813 Days |
Comparison: The null hypothesis was that there was no difference between the 2 treatment groups. The alternative hypothesis was that progression-free survival was longer in the fludarabine+cyclophosphamide+rituximab (FCR) group.p-value: 0.021895% CI: [0.6, 0.96]Log Rank
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population for patients with a Best Overall Response of Complete Response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Disease-free Survival (DFS) | 1285 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Disease-free Survival (DFS) | 1204 Days |
p-value: 0.8842Log Rank
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Event-free Survival (EFS) | 586 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Event-free Survival (EFS) | 874 Days |
p-value: 0.0002Log Rank
Secondary
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.
Time frame: Median observation time was approximately 5 years
Population: Participants from the Intent-to-treat population, all randomized participants, with complete or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Duration of Response | 869.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Duration of Response | 1333.0 Days |
p-value: 0.000795% CI: [0.51, 0.84]Log Rank
Secondary
Final Analysis: Percentage of Participants With Complete Response
Complete response was defined as the disappearance of all signs of cancer in response to treatment.
Time frame: Median observation time was approximately 5 years
Population: Intent-to-treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Percentage of Participants With Complete Response | 13.4 Percentage of participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Percentage of Participants With Complete Response | 25.0 Percentage of participants |
p-value: 0.000595% CI: [1.39, 3.35]Chi-squared
Secondary
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.
Time frame: Median observation time was approximately 5 years
Population: Participants from the Intent-to-treat population, all randomized participants, with complete response. .
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Disease-Free Survival Event | 1285.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Disease-Free Survival Event | 1803.0 Days |
p-value: 0.308595% CI: [0.46, 1.28]Log Rank
Secondary
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.
Time frame: Median observation time was approximately 5 years
Population: Participants from the Intent-to-treat population, all randomized participants, who had an EFS event. Participants who did not have an ESF event at the time of the final analysis were censored at the date of the last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Event-Free Survival Event | 630.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Event-Free Survival Event | 932.0 Days |
p-value: <0.000195% CI: [0.54, 0.79]Log Rank
Secondary
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.
Time frame: Median observation time was approximately 5 years
Population: Participants from the Intent-to-treat population,all randomized participants, who started a new treatment for CLL or died.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment | 1085.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment | 1625.0 Days |
p-value: 0.000295% CI: [0.55, 0.84]Log Rank
Secondary
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.
Time frame: Median observation time was approximately 5 years
Population: The analysis included only those participants from the Intent-to-treat population,all randomized participants, who died. Participants who had not died at the time of the final analysis were censored at the date of the last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Overall Survival Event | 2056.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Overall Survival Event | 2167.0 Days |
p-value: 0.597695% CI: [0.74, 1.19]Log Rank
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population with a Best Overall Response of Complete Response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Disease-free Survival (DFS) Events | Patients with event | 10 participants |
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Disease-free Survival (DFS) Events | Patients without event | 26 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Disease-free Survival (DFS) Events | Patients with event | 19 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Disease-free Survival (DFS) Events | Patients without event | 48 participants |
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Event-free Survival (EFS) Events | Patients with event | 162 participants |
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Event-free Survival (EFS) Events | Patients without events | 114 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Event-free Survival (EFS) Events | Patients with event | 134 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Event-free Survival (EFS) Events | Patients without events | 142 participants |
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Overall Survival (OS) Events | Patients with event | 68 participants |
| Fludarabine+Cyclophosphamide (FC) | Number of Participants With Overall Survival (OS) Events | Patients without events | 208 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Overall Survival (OS) Events | Patients with event | 62 participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Number of Participants With Overall Survival (OS) Events | Patients without events | 214 participants |
Secondary
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.
Time frame: Mean observation time at time of analysis was approximately 26 months
Population: Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Overall Survival (OS) | 1580 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Overall Survival (OS) | NA Days |
p-value: 0.2874Log Rank