Lymphocytic Leukemia, Chronic
Conditions
Brief summary
This single arm study will assess the efficacy and safety of MabThera + chlorambucil as induction therapy, followed in responders by maintenance therapy or observation in elderly patients with previously untreated chronic lymphocytic leukemia. During the induction phase patients will receive 2 x 4 weekly courses of chlorambucil followed by 8 x 4 weekly courses of chlorambucil + MabThera. Subsequently, responders will be randomized to receive 12 doses of MabThera given every 8 weeks, or no further treatment. The anticipated time on study treatment is 2+ years, and the target sample size is \<100 individuals.
Interventions
DRUGrituximab [MabThera/Rituxan]
375mg/m2 iv on day 1 of course 3; 500mg/m2 iv on day 1 of courses 4-8 (induction phase); 375mg/m2 iv every 8 weeks (maintenance phase).
DRUGchlorambucil
8mg/m2 po on days 1-7 of courses 1-8
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients, \>=60 years of age; * CD20+ chronic lymphocytic leukemia (CLL); * no previous treatment for CLL; * ECOG performance status 0-1.
Exclusion criteria
* co-morbid conditions requiring long term use of systemic corticosteroids during study treatment; * history of severe cardiac disease; * transformation to aggressive B-cell malignancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Documented CR, CRi, or PR at the End of Induction Treatment | Month 10 | CR defined as: 1) laboratory CR: peripheral blood lymphocytes (PBL) less than (\<) 4000/microliter (μL), neutrophils (PMN) greater than (\>) 1500/μL, platelets \>100,000/μL, and hemoglobin (Hb) \>11 grams per deciliter (g/dL); 2) clinical CR: lymph nodes (LN) \<1.5 centimeter (cm), and no constitutional symptoms, hepatomegaly (HM) or splenomegaly (SM); 3) instrumental CR: LN \<1.5 cm and no HM/SM, and 4) bone marrow (BM) CR: normocellular aspirate/biopsy for participant age \<30 percent (%) lymphocytes, and no B cell lymphoid nodules. CRi was defined as CR with anemia, thrombocytopenia, or neutropenia not related to chronic lymphocytic leukemia (CLL), with no clonal infiltrate in aspirate or biopsy. PR defined as: a 50% decrease in PBL, a 50% decrease in LN size, no increase in LN size, no new enlarged LN, a 50% reduction from baseline (BL) in the HM/SM, and 1 of the following: PMN \>1500/μL, platelets \>100,000/μL or \>50% improvement from BL, and Hb \>11.0 g/dL or \>50% improvement from BL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Documented CR, CRi, or PR at the End of Study | Month 35 | CR defined as: 1) laboratory CR: PBL \<4000/μL, PMN \> 1500/μL, platelets \> 100,000/μL, and Hb \> 11 g/dL; 2) clinical CR: LN \< 1.5 cm, and no constitutional symptoms, HM or SM; 3) instrumental CR: LN \< 1.5 cm and no HM/SM, and 4) bone marrow CR: normocellular aspirate/biopsy for participant age \< 30% lymphocytes, and no B cell lymphoid nodules. CRi was defined as CR with anemia, thrombocytopenia, or neutropenia not related to CLL, with no clonal infiltrate in aspirate or biopsy. PR defined as: a 50% decrease in PBL, a 50% decrease in LN size, no increase in LN size, no new enlarged LN, a 50% reduction from BL in the HM/SM, and 1 of the following: PMN \> 1500/μL, platelets \> 100,000/μL or \> 50% improvement from BL, and Hb \>11.0 g/dL or \> 50% improvement from BL. |
| Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | Month 10 | CR, CRi, and PR as previously defined. PD was defined by 1 of the following: 1) lymphadenopathy: any new lesion, HM/SM, or other organ infiltrates, or a greater than or equal to (≥) 50% increase in greatest diameter of any previously noted lesion; 2) a ≥ 50% increase in previously noted HM/SM, or new appearance of HM/SM; 3) a ≥ 50% increase in blood lymphocyte count with at least 5000 B lymphocytes/μL; 4) transformation to a more aggressive histology, e.g., Richter's syndrome; or 5) occurrence of cytopenia attributable to CLL. SD was defined by the absence of necessary criteria to achieve CR or PR, but no advancement to PD. Relapse was defined by a previously noted CR or PR with advancement to PD after a period of ≥ 6 months. Nodular PR was defined by the presence of residual lymphoid nodules. |
| Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | Month 35 | CR, and PR as previously defined. PD was defined by 1 of the following: 1) lymphadenopathy: any new lesion, HM/SM, or other organ infiltrates, or a ≥ 50% increase in greatest diameter of any previously noted lesion; 2) a ≥50% increase in previously noted HM/SM, or new appearance of HM/SM; 3) a ≥50% increase in blood lymphocyte count with at least 5000 B lymphocytes/μL; 4) transformation to a more aggressive histology, e.g., Richter's syndrome; or 5) occurrence of cytopenia attributable to CLL. SD was defined by the absence of necessary criteria to achieve CR or PR, but no advancement to PD. Relapse was defined by a previously noted CR or PR with advancement to PD after a period of ≥6 months. Nodular PR was defined by the presence of residual lymphoid nodules. |
| Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment | Month 10 | Immunophenotypic CR was defined as the absence of minimal residual disease (MRD) evaluated in participants with CR by 4-color flow cytometry of PB and BM B cells to confirm that tissue was comprised of non-CLL cells. Molecular CR was defined as the absence of MRD evaluated in participants with CR by quantitative polymerase chain reaction (PCR) in PB and BM B cells to confirm that tissue was comprised of non-CLL cells. |
| Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | Month 35 | CR, CRi, PR, SD, PD, relapse, and nodular PR as previously defined. |
| Percentage of Participants With Immunophenotypic CR - BM or Immunophenotypic CR - PB at the End of Study | Month 35 | Immunophenotypic CR was defined as the absence of MRD evaluated in participants who achieved CR by 4-color flow cytometry of PB and BM B cells to confirm that tissue was comprised of non-CLL cells. |
| Percentage of Participants With Molecular CR - BM or Molecular CR - PB at the End of Study | Month 35 | Molecular CR was defined as the absence of MRD evaluated in participants who achieved CR by quantitative PCR in PB and BM B cells to confirm that tissue was comprised of non-CLL cells. |
| Number of Participants With Disease Progression, Relapse, Death, Withdrawal Because of an Adverse Event (AE), or New CLL Treatment | Screening, Days 1 and 15 of Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Event-free Survival (EFS) was defined as the time from the first dose of study treatment to the date of first documentation of disease progression, relapse for participants with previous CR, death due to any cause, withdrawal due to AE, or beginning new CLL treatment. CR and PD as previously defined. Participants were censored at the time of data cut-off to the most recent date of disease assessment. Participants without a post-BL disease assessment were censored at the time of first dose of study treatment. |
| EFS | Screening, Days 1 and 15 of Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The median time, in days, from the the date of first dose of study treatment to the date of first documentation of disease progression, relapse for participants with CR, death due to any cause, withdrawal due to AE, or new CLL treatment. CR and PD as previously defined. Participants were censored at the time of data cut-off to the most recent date of disease assessment. Participants without a post-BL disease assessment were censored at the time of first dose if study treatment. The 95% CI was determined using Kaplan-Meier methodology. |
| Number of Participants With Disease Progression or Death | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Progression-free survival (PFS) was defined as the time from the first dose of study treatment to the first documentation of disease progression or death. PD as previously defined. Participants who were withdrawn from the study without documented disease progression were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without a post-BL tumor assessment, but known to be alive, were censored at the time of the first dose of study treatment. |
| PFS | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The median time, in days, from the date of the first dose of study treatment to the date of first documentation of disease progression or death. CR and PD as previously defined. Participants who were withdrawn from the study without documented disease progression were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without a post-BL tumor assessment, but known to be alive, were censored at the time of the first dose of study treatment. The 95% CI was determined using Kaplan-Meier methodology. |
| Number of Participants With New CLL Treatment or Death | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Time to new CLL treatment (TTNT) was defined as the time from the first dose of study treatment to the date of new CLL treatment received or the date of death from any cause. Participants who did not receive new CLL treatment and were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. |
| Time to Next Treatment (TTNT) | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The mean time, in days, from the date of the first dose of study treatment to the date of new CLL treatment or the date of death from any cause. Participants who did not receive new CLL treatment and were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. Mean survival time and it's standard error (SE) were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. |
| Number of Participants Who Died | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Overall Survival (OS) was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. Participants were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. |
| OS | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The mean time, in days, from the date of the first dose of study treatment to the date of death due to any cause. Participants were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. The mean survival time and it's SE were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. |
| Number of Participants With PD or Death After a Confirmed CR, CRi, or PR | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Duration of response was defined as the time from the date of the first documented CR, CRi, or PR to the date of disease progression or death. CR, CRi, PR, and PD as previously defined. Participants with no documented PD after CR, CRi, or PR were censored at the last date at which they were known to have had CR, CRi, or PR, respectively. |
| Duration of Response | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The mean time, in days, from the date of first documented CR, CRi or PR to the date disease progression or death. CR, CRi, PR, and PD as previously defined. Participants with no documented PD after CR, CRi, or PR were censored at the last date at which they were known to have had CR, CRi, or PR, respectively. |
| Number of Participants With PD or Death After a Confirmed CR/CRi | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | Disease-free survival was defined at the time from the date of first documented CR or CRi to the date of disease progression or death. CR, CRi, and PD as previously defined. Participants with no documented PD after CR or CRi were censored on the last date at which they were known to have had CR or CRi. |
| Disease-Free Survival | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | The mean time, in days, from the date of first documented CR or CRi to the date of disease progression or death. CR, CRi, and PD as previously defined. Participants with no documented PD after CR or CRi were censored on the last date at which they were known to have had CR or CRi. In both groups, the mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CLB + R: Not Randomized Participants began a 8-month induction treatment phase where they received 8 (4-week) courses of treatment consisting of: CLB, 8 mg/m\^2, PO as film-coated tablets, daily (dose could be divided in halves or thirds to prevent nausea), on Days 1-7 of Courses 1 and 2, Days 2-8 of Course 3, and Days 1-7 of Courses 4-8; and rituximab, 375 mg/m\^2, IV, on Day 1 of Course 3, and 500 mg/m\^2, IV, on Day 1 of Courses 4-8. Participants who completed the induction treatment with CR, CRi, or PR were randomized to receive either rituximab, 375 mg/m\^2, IV, every 8 weeks for up to 24 months, or to be observed for up to 24 months with no further treatment. | 31 |
| CLB + R: Maintenance Treatment Participants completed an 8-month induction treatment phase where they received 8 (4-week) courses of treatment consisting of: CLB, 8 mg/m\^2, PO as film-coated tablets, daily (dose could be divided in halves or thirds to prevent nausea), on Days 1-7 of Courses 1 and 2, Days 2-8 of Course 3, and Days 1-7 of Courses 4-8; and rituximab, 375 mg/m\^2, IV, on Day 1 of Course 3, and 500 mg/m\^2, IV, on Day 1 of Courses 4-8. Participants with CR, CRi, or PR were randomized to receive rituximab, 375 mg/m\^2, IV, once every 8 weeks for a total of 12 infusions for up to 24 months. | 34 |
| CLB + R: Observation Participants completed an 8-month induction treatment phase where they received 8 (4-week) courses of treatment consisting of: CLB, 8 mg/m\^2, PO as film-coated tablets, daily (dose could be divided in halves or thirds to prevent nausea), on Days 1-7 of Courses 1 and 2, Days 2-8 of Course 3, and Days 1-7 of Courses 4-8; and rituximab, 375 mg/m\^2, IV, on Day 1 of Course 3, and 500 mg/m\^2, IV, on Day 1 of Courses 4-8. Participants with CR, CRi, or PR were randomized to be observed for up to 24 months and received no further treatment. | 32 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Induction Treatment Phase | Adverse Event | 14 | 0 | 0 | 0 |
| Induction Treatment Phase | Disease progression/relapse/stable | 4 | 0 | 0 | 0 |
| Induction Treatment Phase | Non-compliance | 1 | 0 | 0 | 0 |
| Induction Treatment Phase | Physician Decision | 2 | 0 | 0 | 0 |
| Induction Treatment Phase | Protocol Violation | 2 | 0 | 0 | 0 |
| Induction Treatment Phase | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Maintenance Treatment/Observation Phase | Adverse Event | 0 | 1 | 2 | 0 |
| Maintenance Treatment/Observation Phase | Disease progression/relapse/stable | 0 | 4 | 5 | 11 |
| Maintenance Treatment/Observation Phase | Other | 0 | 1 | 0 | 0 |
| Maintenance Treatment/Observation Phase | Protocol Violation | 0 | 1 | 0 | 0 |
| Maintenance Treatment/Observation Phase | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | CLB + R: Not Randomized | CLB + R: Maintenance Treatment | CLB + R: Observation | Total |
|---|---|---|---|---|
| Age, Continuous | 74.7 years STANDARD_DEVIATION 6.5 | 69.8 years STANDARD_DEVIATION 5.4 | 70.2 years STANDARD_DEVIATION 5.1 | 71.7 years STANDARD_DEVIATION 6.1 |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 9 Participants | 32 Participants |
| Sex: Female, Male Male | 18 Participants | 24 Participants | 23 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 73 / 97 | 25 / 34 | 17 / 32 |
| serious Total, serious adverse events | 17 / 97 | 4 / 34 | 4 / 32 |
Outcome results
Primary
Percentage of Participants With Documented CR, CRi, or PR at the End of Induction Treatment
CR defined as: 1) laboratory CR: peripheral blood lymphocytes (PBL) less than (\<) 4000/microliter (μL), neutrophils (PMN) greater than (\>) 1500/μL, platelets \>100,000/μL, and hemoglobin (Hb) \>11 grams per deciliter (g/dL); 2) clinical CR: lymph nodes (LN) \<1.5 centimeter (cm), and no constitutional symptoms, hepatomegaly (HM) or splenomegaly (SM); 3) instrumental CR: LN \<1.5 cm and no HM/SM, and 4) bone marrow (BM) CR: normocellular aspirate/biopsy for participant age \<30 percent (%) lymphocytes, and no B cell lymphoid nodules. CRi was defined as CR with anemia, thrombocytopenia, or neutropenia not related to chronic lymphocytic leukemia (CLL), with no clonal infiltrate in aspirate or biopsy. PR defined as: a 50% decrease in PBL, a 50% decrease in LN size, no increase in LN size, no new enlarged LN, a 50% reduction from baseline (BL) in the HM/SM, and 1 of the following: PMN \>1500/μL, platelets \>100,000/μL or \>50% improvement from BL, and Hb \>11.0 g/dL or \>50% improvement from BL.
Time frame: Month 10
Population: Intent to treat (ITT) population: all consented participants who received at least 1 dose of rituximab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Percentage of Participants With Documented CR, CRi, or PR at the End of Induction Treatment | 82.4 percentage of participants |
Comparison: Analysis compared responders and non-responders.p-value: 0.0008Chi-squared
Secondary
Disease-Free Survival
The mean time, in days, from the date of first documented CR or CRi to the date of disease progression or death. CR, CRi, and PD as previously defined. Participants with no documented PD after CR or CRi were censored on the last date at which they were known to have had CR or CRi. In both groups, the mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: All randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLB + R: All Participants | Disease-Free Survival | 699.91 days | Standard Error 68.89 |
| CLB + R: Observation | Disease-Free Survival | 732.28 days | Standard Error 63.37 |
Secondary
Duration of Response
The mean time, in days, from the date of first documented CR, CRi or PR to the date disease progression or death. CR, CRi, PR, and PD as previously defined. Participants with no documented PD after CR, CRi, or PR were censored at the last date at which they were known to have had CR, CRi, or PR, respectively.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: All randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLB + R: All Participants | Duration of Response | 840.87 days | Standard Error 29.71 |
| CLB + R: Observation | Duration of Response | 747.82 days | Standard Error 55.77 |
p-value: 0.2712Log Rank
Secondary
EFS
The median time, in days, from the the date of first dose of study treatment to the date of first documentation of disease progression, relapse for participants with CR, death due to any cause, withdrawal due to AE, or new CLL treatment. CR and PD as previously defined. Participants were censored at the time of data cut-off to the most recent date of disease assessment. Participants without a post-BL disease assessment were censored at the time of first dose if study treatment. The 95% CI was determined using Kaplan-Meier methodology.
Time frame: Screening, Days 1 and 15 of Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CLB + R: All Participants | EFS | 1051 days |
Secondary
Number of Participants Who Died
Overall Survival (OS) was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. Participants were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants Who Died | 8 participants |
Secondary
Number of Participants With Disease Progression or Death
Progression-free survival (PFS) was defined as the time from the first dose of study treatment to the first documentation of disease progression or death. PD as previously defined. Participants who were withdrawn from the study without documented disease progression were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without a post-BL tumor assessment, but known to be alive, were censored at the time of the first dose of study treatment.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants With Disease Progression or Death | 35 participants |
Secondary
Number of Participants With Disease Progression, Relapse, Death, Withdrawal Because of an Adverse Event (AE), or New CLL Treatment
Event-free Survival (EFS) was defined as the time from the first dose of study treatment to the date of first documentation of disease progression, relapse for participants with previous CR, death due to any cause, withdrawal due to AE, or beginning new CLL treatment. CR and PD as previously defined. Participants were censored at the time of data cut-off to the most recent date of disease assessment. Participants without a post-BL disease assessment were censored at the time of first dose of study treatment.
Time frame: Screening, Days 1 and 15 of Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants With Disease Progression, Relapse, Death, Withdrawal Because of an Adverse Event (AE), or New CLL Treatment | 43 participants |
Secondary
Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment
Immunophenotypic CR was defined as the absence of minimal residual disease (MRD) evaluated in participants with CR by 4-color flow cytometry of PB and BM B cells to confirm that tissue was comprised of non-CLL cells. Molecular CR was defined as the absence of MRD evaluated in participants with CR by quantitative polymerase chain reaction (PCR) in PB and BM B cells to confirm that tissue was comprised of non-CLL cells.
Time frame: Month 10
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment | Immunophenotypic CR - BM | 2 participants |
| CLB + R: All Participants | Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment | Immunophenotypic CR - PB | 3 participants |
| CLB + R: All Participants | Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment | Molecular CR - BM | 0 participants |
| CLB + R: All Participants | Number of Participants With Immunophenotypic CR - BM, Immunophenotypic CR - Peripheral Blood (PB), Molecular CR - BM, or Molecular CR - PB at the End of Induction Treatment | Molecular CR - PB | 0 participants |
Secondary
Number of Participants With New CLL Treatment or Death
Time to new CLL treatment (TTNT) was defined as the time from the first dose of study treatment to the date of new CLL treatment received or the date of death from any cause. Participants who did not receive new CLL treatment and were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants With New CLL Treatment or Death | 22 participants |
Secondary
Number of Participants With PD or Death After a Confirmed CR/CRi
Disease-free survival was defined at the time from the date of first documented CR or CRi to the date of disease progression or death. CR, CRi, and PD as previously defined. Participants with no documented PD after CR or CRi were censored on the last date at which they were known to have had CR or CRi.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: All randomized participants with a confirmed CR or CRi were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants With PD or Death After a Confirmed CR/CRi | 2 participants |
| CLB + R: Observation | Number of Participants With PD or Death After a Confirmed CR/CRi | 8 participants |
Secondary
Number of Participants With PD or Death After a Confirmed CR, CRi, or PR
Duration of response was defined as the time from the date of the first documented CR, CRi, or PR to the date of disease progression or death. CR, CRi, PR, and PD as previously defined. Participants with no documented PD after CR, CRi, or PR were censored at the last date at which they were known to have had CR, CRi, or PR, respectively.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Number of Participants With PD or Death After a Confirmed CR, CRi, or PR | 11 participants |
| CLB + R: Observation | Number of Participants With PD or Death After a Confirmed CR, CRi, or PR | 15 participants |
Secondary
OS
The mean time, in days, from the date of the first dose of study treatment to the date of death due to any cause. Participants were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. The mean survival time and it's SE were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLB + R: All Participants | OS | 1135.04 days | Standard Error 24.25 |
Secondary
Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study
CR, CRi, PR, SD, PD, relapse, and nodular PR as previously defined.
Time frame: Month 35
Population: All randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | CR | 29.4 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | CRi | 0.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | PR | 26.4 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | CR | 18.7 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | CRi | 0.0 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, CRi, PR, SD, PD, or Relapse at the End of Study | PR | 12.5 percentage of participants |
Secondary
Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment
CR, CRi, and PR as previously defined. PD was defined by 1 of the following: 1) lymphadenopathy: any new lesion, HM/SM, or other organ infiltrates, or a greater than or equal to (≥) 50% increase in greatest diameter of any previously noted lesion; 2) a ≥ 50% increase in previously noted HM/SM, or new appearance of HM/SM; 3) a ≥ 50% increase in blood lymphocyte count with at least 5000 B lymphocytes/μL; 4) transformation to a more aggressive histology, e.g., Richter's syndrome; or 5) occurrence of cytopenia attributable to CLL. SD was defined by the absence of necessary criteria to achieve CR or PR, but no advancement to PD. Relapse was defined by a previously noted CR or PR with advancement to PD after a period of ≥ 6 months. Nodular PR was defined by the presence of residual lymphoid nodules.
Time frame: Month 10
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | CR | 16.5 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | CRi | 2.4 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | PR | 60.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | SD | 4.7 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | PD | 3.5 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | Relapse | 0.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | Nodular PR | 3.5 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, CRi, PR, Stable Disease (SD), Progressive Disease (PD), Relapse, or Nodular PR at the End of Induction Treatment | Unknown | 9.4 percentage of participants |
Secondary
Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study
CR, and PR as previously defined. PD was defined by 1 of the following: 1) lymphadenopathy: any new lesion, HM/SM, or other organ infiltrates, or a ≥ 50% increase in greatest diameter of any previously noted lesion; 2) a ≥50% increase in previously noted HM/SM, or new appearance of HM/SM; 3) a ≥50% increase in blood lymphocyte count with at least 5000 B lymphocytes/μL; 4) transformation to a more aggressive histology, e.g., Richter's syndrome; or 5) occurrence of cytopenia attributable to CLL. SD was defined by the absence of necessary criteria to achieve CR or PR, but no advancement to PD. Relapse was defined by a previously noted CR or PR with advancement to PD after a period of ≥6 months. Nodular PR was defined by the presence of residual lymphoid nodules.
Time frame: Month 35
Population: All randomized participants who were assessed at Month 35 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | CR | 32.3 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | PR | 29.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | SD | 3.2 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | PD | 29.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | Relapse | 6.5 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | Nodular PR | 0.0 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | Relapse | 14.3 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | CR | 21.4 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | PD | 39.3 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | PR | 14.3 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | Nodular PR | 3.6 percentage of participants |
| CLB + R: Observation | Percentage of Participants With CR, PR, SD, PD, Relapse, or Nodular PR at the End of Study | SD | 7.1 percentage of participants |
Secondary
Percentage of Participants With Documented CR, CRi, or PR at the End of Study
CR defined as: 1) laboratory CR: PBL \<4000/μL, PMN \> 1500/μL, platelets \> 100,000/μL, and Hb \> 11 g/dL; 2) clinical CR: LN \< 1.5 cm, and no constitutional symptoms, HM or SM; 3) instrumental CR: LN \< 1.5 cm and no HM/SM, and 4) bone marrow CR: normocellular aspirate/biopsy for participant age \< 30% lymphocytes, and no B cell lymphoid nodules. CRi was defined as CR with anemia, thrombocytopenia, or neutropenia not related to CLL, with no clonal infiltrate in aspirate or biopsy. PR defined as: a 50% decrease in PBL, a 50% decrease in LN size, no increase in LN size, no new enlarged LN, a 50% reduction from BL in the HM/SM, and 1 of the following: PMN \> 1500/μL, platelets \> 100,000/μL or \> 50% improvement from BL, and Hb \>11.0 g/dL or \> 50% improvement from BL.
Time frame: Month 35
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLB + R: All Participants | Percentage of Participants With Documented CR, CRi, or PR at the End of Study | 55.9 percentage of participants |
| CLB + R: Observation | Percentage of Participants With Documented CR, CRi, or PR at the End of Study | 34.4 percentage of participants |
p-value: 0.0795Chi-squared
Secondary
Percentage of Participants With Immunophenotypic CR - BM or Immunophenotypic CR - PB at the End of Study
Immunophenotypic CR was defined as the absence of MRD evaluated in participants who achieved CR by 4-color flow cytometry of PB and BM B cells to confirm that tissue was comprised of non-CLL cells.
Time frame: Month 35
Population: All randomized participants, only participants with a confirmed CR were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Percentage of Participants With Immunophenotypic CR - BM or Immunophenotypic CR - PB at the End of Study | Immunophenotypic CR - BM | 10.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With Immunophenotypic CR - BM or Immunophenotypic CR - PB at the End of Study | Immunophenotypic CR - PB | 30.0 percentage of participants |
Secondary
Percentage of Participants With Molecular CR - BM or Molecular CR - PB at the End of Study
Molecular CR was defined as the absence of MRD evaluated in participants who achieved CR by quantitative PCR in PB and BM B cells to confirm that tissue was comprised of non-CLL cells.
Time frame: Month 35
Population: All randomized participants analyzed for the given parameter at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLB + R: All Participants | Percentage of Participants With Molecular CR - BM or Molecular CR - PB at the End of Study | Molecular CR - BM | 100.0 percentage of participants |
| CLB + R: All Participants | Percentage of Participants With Molecular CR - BM or Molecular CR - PB at the End of Study | Molecular CR - PB | 33.3 percentage of participants |
Secondary
PFS
The median time, in days, from the date of the first dose of study treatment to the date of first documentation of disease progression or death. CR and PD as previously defined. Participants who were withdrawn from the study without documented disease progression were censored at the date of the last tumor assessment when the participant was known to be progression-free. Participants without a post-BL tumor assessment, but known to be alive, were censored at the time of the first dose of study treatment. The 95% CI was determined using Kaplan-Meier methodology.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CLB + R: All Participants | PFS | 1059 days |
Secondary
Time to Next Treatment (TTNT)
The mean time, in days, from the date of the first dose of study treatment to the date of new CLL treatment or the date of death from any cause. Participants who did not receive new CLL treatment and were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without a follow-up assessment were censored at the day of last dose of study treatment. Mean survival time and it's standard error (SE) were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.
Time frame: Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLB + R: All Participants | Time to Next Treatment (TTNT) | 1048.19 days | Standard Error 31.86 |