Lymphocytic Leukemia, Chronic
Conditions
Brief summary
This study will evaluate the efficacy and safety of intense combination treatment including MabThera/Rituxan (rituximab), followed by MabThera/Rituxan maintenance therapy in patients with B-cell CLL who are naive to chemotherapy. The anticipated time on study treatment is 2.5 years.
Interventions
DRUGrituximab [MabThera/Rituxan]
Every 4 weeks for 6 cycles of induction, followed by maintenance therapy every 3 months x 8
DRUGfludarabine
Every 4 weeks, 6 cycles
DRUGcyclophosphamide
Every 4 weeks, 3 cycles
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, \>/= 18 years of age * B-cell CLL * No previous chemotherapy, radiotherapy, or immunotherapy
Exclusion criteria
* Reduced organ function, or bone marrow dysfunction not due to CLL * Patients with a history of other malignancies within 2 years prior to study entry, except for adequately treated cancer in situ of the cervix, or basal or squamous cell skin cancer * Patients with a history of severe cardiac disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Best Clinical Response of Clinical Remission (CR) | Weeks 1, 5, 9, 12, 13, 17, 21 and 24 | Best clinical response was determined according to the National Cancer Institute (NCI) Clinical and Clinical plus (+) Radiological evaluations by central response assessment. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of chronic lymphocytic lymphoma (CLL) with additional computerized tomography (CT) scan evaluation of lymphadenopathy. Per NCI guidelines, CR requires all of the following criteria at least 2 months after the last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils greater than (\>)1500 per microliter (/µL), platelets (PL) \>100,000/µL, hemoglobin (Hb) \>11.0 grams per deciliter (g/dL), lymphocytes (LC) (less than) \<4000/µL, bone marrow (BM) sample must be normocellular for age, \<30% LC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | Weeks 12 and 24 and at Final Staging (Week 4 after last maintenance dose) | Best clinical response was determined according to the NCI clinical evaluation and through radiological assessment. CR, CRi, CRu, partial remission (PR), partial remission with toxicity associated (PRTox), progressive disease (PD), and stable disease (SD) were evaluated. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of CLL with additional CT scan evaluation of lymphadenopathy during the treatment period (Radiological). Response assessment for interim (Week 12), end of induction (Week 24) and at Final Staging (4 weeks after last maintenance dose). Last observation carried forward (LOCF) method was used for missing data. Percentages are based on the number of nonmissing observations within each stratum. |
| Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | Weeks 12 and 24 and at Final Staging (Week 4 after last maintenance dose) | Best clinical response was determined according to the NCI clinical evaluation and through radiological assessment. CR, CRi, CRu, PR, PRTox, PD, and SD were evaluated. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of CLL with additional CT scan evaluation of lymphadenopathy during the treatment period (Radiological). Response assessment for interim (Week 12), end of induction (Week 24) and at Final Staging (4 weeks after last maintenance dose). LOCF method was used for missing data. Percentages are based on the number of nonmissing observations within each stratum. |
| Time to Next Treatment - Percentage of Participants With an Event | Weeks 1, 5, 9, 12, 13, 17, 21 and 24 and every 8 weeks for 64 Weeks and every 6 months | Time to next treatment was calculated as the number of days from either discontinuation of the study drug or the administration of the last dose, until the participants needed next treatment. |
| Time to Next Treatment - Time to Event | Weeks 1, 5, 9, 12, 13, 17, 21 and 24 and every 8 weeks for 64 Weeks and every 6 months | Time to next treatment was calculated as the number of days from either discontinuation of the study drug or the administration of the last dose, until the participants needed next treatment. |
| Percentage of Participants With Adverse Events (AEs) | Day 1 of Cycles 1, 2, 3, 4, 5, and 6 to 28 days after the last trial medication. | AEs were recorded from the date of first medication administration until 28 days after the last trial medication. |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab, Fludarabine, Cyclophosphamide Induction Phase Cycle 1 (4-week cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1-3 and rituximab 375 mg/m\^2 IV on Day 4. Induction Phase Cycles 2 and 3 (4-week cycles): Participants received rituximab 500 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1-3 Induction Phase Cycles 4 to 6 (4-week cycles): Participants received rituximab 500 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV on Days 1-5. Maintenance Phase (Cycles 1-8; 12-week cycles): 8 weeks after the end of the last induction cycle, participants received maintenance therapy with rituximab 375 mg/m\^2, IV once every 12 weeks for a total of 8 infusions (maximum 2 years). | 43 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Death | 2 |
| Overall Study | Other | 9 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Rituximab, Fludarabine, Cyclophosphamide |
|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 43 |
| serious Total, serious adverse events | 30 / 43 |
Outcome results
Primary
Percentage of Participants With a Best Clinical Response of Clinical Remission (CR)
Best clinical response was determined according to the National Cancer Institute (NCI) Clinical and Clinical plus (+) Radiological evaluations by central response assessment. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of chronic lymphocytic lymphoma (CLL) with additional computerized tomography (CT) scan evaluation of lymphadenopathy. Per NCI guidelines, CR requires all of the following criteria at least 2 months after the last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils greater than (\>)1500 per microliter (/µL), platelets (PL) \>100,000/µL, hemoglobin (Hb) \>11.0 grams per deciliter (g/dL), lymphocytes (LC) (less than) \<4000/µL, bone marrow (BM) sample must be normocellular for age, \<30% LC.
Time frame: Weeks 1, 5, 9, 12, 13, 17, 21 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With a Best Clinical Response of Clinical Remission (CR) | NCI Clinical | 73.7 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With a Best Clinical Response of Clinical Remission (CR) | NCI Clinical (including CRu, CRi) | 94.7 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With a Best Clinical Response of Clinical Remission (CR) | NCI Clinical + Radiological | 63.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With a Best Clinical Response of Clinical Remission (CR) | NCI Clinical + Radiological (including CRu, CRi) | 78.9 percentage of participants |
Secondary
Percentage of Participants With Adverse Events (AEs)
AEs were recorded from the date of first medication administration until 28 days after the last trial medication.
Time frame: Day 1 of Cycles 1, 2, 3, 4, 5, and 6 to 28 days after the last trial medication.
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) | Any AE | 100 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) | Related AE | 93.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) | Severe AE | 76.7 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) | SAE | 62.8 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) | Pregnancy | 0.0 percentage of participants |
Secondary
Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment)
Best clinical response was determined according to the NCI clinical evaluation and through radiological assessment. CR, CRi, CRu, partial remission (PR), partial remission with toxicity associated (PRTox), progressive disease (PD), and stable disease (SD) were evaluated. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of CLL with additional CT scan evaluation of lymphadenopathy during the treatment period (Radiological). Response assessment for interim (Week 12), end of induction (Week 24) and at Final Staging (4 weeks after last maintenance dose). Last observation carried forward (LOCF) method was used for missing data. Percentages are based on the number of nonmissing observations within each stratum.
Time frame: Weeks 12 and 24 and at Final Staging (Week 4 after last maintenance dose)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PR, Week 24 | 9.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CR, Week 12 | 41.9 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRu, Week 12 | 16.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRi, Week 12 | 16.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PR, Week 12 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PRTox, Week 12 | 2.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | SD, Week 12 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PD, Week 12 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CR, Week 24 | 30.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | Not evaluable, Week 12 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRu, Week 24 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRi, Week 24 | 37.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PRTox, Week 24 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | SD, Week 24 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PD, Week 24 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | Not evaluable, Week 24 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CR, Final staging | 60.5 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRu, Final staging | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | CRi, Final staging | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PR, Final staging | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PRTox, Final staging | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | SD, Final staging | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | PD, Final staging | 2.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical Assessment) | Not evaluable, Final staging | 11.6 percentage of participants |
Secondary
Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment)
Best clinical response was determined according to the NCI clinical evaluation and through radiological assessment. CR, CRi, CRu, PR, PRTox, PD, and SD were evaluated. Assessment of response was performed according to the NCI revised guidelines for the diagnosis and treatment of CLL with additional CT scan evaluation of lymphadenopathy during the treatment period (Radiological). Response assessment for interim (Week 12), end of induction (Week 24) and at Final Staging (4 weeks after last maintenance dose). LOCF method was used for missing data. Percentages are based on the number of nonmissing observations within each stratum.
Time frame: Weeks 12 and 24 and at Final Staging (Week 4 after last maintenance dose)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CR, Final staging | 48.8 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PRTox, Final staging | 2.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CR, Week 12 | 30.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRu, Week 12 | 4.7 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRi, Week 12 | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PR, Week 12 | 30.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PRTox, Week 12 | 9.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | SD, Week 124 | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PD, Week 12 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | Not evaluable, Week 12 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CR, Week 24 | 23.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRu, Week 24 | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRi, Week 24 | 30.2 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PR, Week 24 | 14.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PRTox, Week 24 | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | SD, Week 24 | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PD, Week 24 | 0.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | Not evaluable, Week 24 | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRu, Final staging | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | CRi, Final staging | 7.0 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PR, Final staging | 11.6 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | SD, Final staging | 2.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | PD, Final staging | 9.3 percentage of participants |
| Rituximab, Fludarabine, Cyclophosphamide | Percentage of Participants With the Best Clinical Response by Visit (Clinical + Radiological Assessment) | Not evaluable, Final staging | 11.6 percentage of participants |
Secondary
Time to Next Treatment - Percentage of Participants With an Event
Time to next treatment was calculated as the number of days from either discontinuation of the study drug or the administration of the last dose, until the participants needed next treatment.
Time frame: Weeks 1, 5, 9, 12, 13, 17, 21 and 24 and every 8 weeks for 64 Weeks and every 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Time to Next Treatment - Percentage of Participants With an Event | 37.2 percentage of participants |
Secondary
Time to Next Treatment - Time to Event
Time to next treatment was calculated as the number of days from either discontinuation of the study drug or the administration of the last dose, until the participants needed next treatment.
Time frame: Weeks 1, 5, 9, 12, 13, 17, 21 and 24 and every 8 weeks for 64 Weeks and every 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab, Fludarabine, Cyclophosphamide | Time to Next Treatment - Time to Event | 423.3 days | Standard Deviation 398.5 |