A Study of MabThera (Rituximab) Plus Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia.

Study Overview
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Brief Summary
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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.

Official Title
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A Study of Chlorambucil Plus MabThera as Induction Therapy Followed in Responders by Maintenance Therapy Versus Observation on Response Rate in Patients >=60 Years With Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Lymphocytic Leukemia, Chronic

Intervention / Treatment
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* Drug: rituximab [MabThera/Rituxan]
* Drug: chlorambucil


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: rituximab [MabThera/Rituxan]<br>* 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).<br>Drug: chlorambucil<br>* 8mg/m2 po on days 1-7 of courses 1-8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 35 | 
| 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. | Month 10 | 
| 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. | Month 35 | 
| 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. | Month 10 | 
| 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. | Month 35 | 
| 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. | Month 35 | 
| 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. | Month 35 | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | 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 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | 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 | 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. | 
| 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. | 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 | 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. | Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months. |