A Study of MabThera Added to Bendamustine or Chlorambucil in Patients With Chronic Lymphocytic Leukemia (MaBLe)

Study Overview
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Brief Summary
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This randomized, open-label, parallel group study will assess the effect on response rate and the safety of MabThera added to either bendamustine or chlorambucil in patients with chronic lymphocytic leukemia. Patients will be randomized to receive six 4-week cycles of either A) MabThera (375mg/m2 iv day 1 of cycle 1, 500mg/m2 iv cycles 2-6) plus bendamustine (90mg/m2 as first-line or 70mg/m2 as second-line therapy, iv on days 1 and 2, cycles 1-6), or B)MabThera plus chlorambucil (10mg/m2 po daily, days 1-7, cycles 1-6). Patients in group B can receive up to 6 further cycles of chlorambucil as monotherapy. Anticipated time on study treatment is 6-12 months, and target sample size is 600-700 individuals.

Official Title
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A Randomized Study to Assess the Effect on Response Rate of MabThera (Rituximab) Added to a Standard Chemotherapy, Bendamustine or Chlorambucil, in Patients With Chronic Lymphocytic Leukemia

Conditions
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Lymphocytic Leukemia, Chronic

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >/=18 years of age chronic lymphocytic leukemia active CLL with progressive Binet stage B or C ineligible for treatment with fludarabine for second line patients, only pretreatment with rituximab and/or chlorambucil is allowed EOCG performance status >/=2 Exclusion Criteria: patients who have relapsed within <12 months of first dose of prior rituximab or chlorambucil first-line therapy previous or planned stem cell transplantation radioimmunotherapy within 6 months prior to starting study treatment transformation to aggressive B-cell malignancy any other concurrent anti-cancer therapy, or glucocorticoid >/=20mg daily prednisolone or equivalent

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: bendamustine<br>* 90mg/m2 (first-line) or 70mg/m2 (second-line) iv, days 1 and 2 every 4 weeks, cycles 1-6<br>Drug: rituximab [MabThera/Rituxan]<br>* 375mg/m2 iv day 1 of cycle 1, followed by 500mg/m2 iv every 4 weeks cycles 2-6<br>|
| Experimental: B<br> | Drug: chlorambucil<br>* 10mg/m2 po days 1-7 every 4 weeks, for up to 12 cycles<br>Drug: rituximab [MabThera/Rituxan]<br>* 375mg/m2 iv day 1 of cycle 1, followed by 500mg/m2 iv every 4 weeks cycles 2-6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Confirmed Complete Response (CR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines in the First-Line Subpopulation After 6 Cycles of Therapy | The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes less than (<) 4 times 10^9 cells per liter (cells/L); absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to chronic lymphocytic leukemia (CLL) involvement; absence of constitutional symptoms; normal complete blood count (CBC) without need for transfusion or exogenous growth factors, as exhibited by neutrophils at least (>/=) 1.5 times 10^9 cells/L, platelets greater than (>) 100 times 10^9 cells/L, and hemoglobin > 11.0 grams per deciliter (g/dL); normocellular bone marrow (BM) aspirate with < 30 percent (%) lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. The percentage of participants achieving confirmed CR was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100. | At least 2 months after completion of therapy (up to 32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Pooled Population After 6 Cycles of Therapy | The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes < 4 times 10^9 cells/L; absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to CLL involvement; absence of constitutional symptoms; normal CBC without need for transfusion or exogenous growth factors, as exhibited by neutrophils >/= 1.5 times 10^9 cells/L, platelets > 100 times 10^9 cells/L, and hemoglobin > 11.0 g/dL; normocellular BM aspirate with < 30% lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. The percentage of participants achieving confirmed CR was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100. | At least 2 months after completion of therapy (up to 32 weeks) | 
| Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Second-Line Subpopulation After 6 Cycles of Therapy | The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes < 4 times 10^9 cells/L; absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to CLL involvement; absence of constitutional symptoms; normal CBC without need for transfusion or exogenous growth factors, as exhibited by neutrophils >/= 1.5 times 10^9 cells/L, platelets > 100 times 10^9 cells/L, and hemoglobin > 11.0 g/dL; normocellular BM aspirate with < 30% lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. The percentage of participants achieving confirmed CR was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100. | At least 2 months after completion of therapy (up to 32 weeks) | 
| Percentage of Participants Achieving a Best Overall Response of CR, CR With Incomplete Marrow Recovery (CRi), Partial Response (PR), or Nodular PR (nPR) in the First-Line Subpopulation | The criteria for CR are identified in previous outcome measure(s). Those fulfilling CR criteria but who have persistent anemia, thrombocytopenia, or neutropenia were considered CRi. The definition of PR required that the following be documented for minimum 2 months: >/= 50% decrease in peripheral blood lymphocytes from Baseline; reduction in lymphadenopathy; >/= 50% reduction in spleen or liver enlargement; and CBC with one of the following without need for transfusion or exogenous growth factors: polymorphonuclear leukocytes >/= 1.5 times 10^9 cells/L, platelets > 100 times 10^9 cells/L or >/= 50% improvement from Baseline, or hemoglobin > 11.0 g/dL or >/= 50% improvement from Baseline. Participants with lymphoid nodules who otherwise met CR criteria were considered nPR. The percentage of participants achieving each level of response was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100. | After 3 and 6 treatment cycles and from Baseline to the end-of-treatment (EOT) visit, completed within 10 days before cutoff for data collection | 
| Percentage of Participants by Disease Response Category in the First-Line Subpopulation | The criteria for CR, CRi, PR, and nPR are identified in previous outcome measure(s). PD was defined by at least one of the following: the presence of lymphadenopathy; an increase in the previously noted enlargement of the liver or spleen by >/= 50% or the de novo appearance of hepatomegaly or splenomegaly; an increase in the number of blood lymphocytes by >/= 50% with >/= 5000 B-cells per microliter (B-cells/mcL); transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Participants not achieving a CR or PR, and who did not exhibit PD, were considered to have stable disease (SD). The percentage of participants achieving each level of response was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed. The rows below are labeled first by the level of response at the end of 6 cycles (C6), then by level of response at the confirmation assessment. | After 6 treatment cycles and at the confirmation of response assessment at least 12 weeks later (up to 36 weeks) | 
| Percentage of Participants Experiencing PD or Death in the First-Line Subpopulation | The criteria for PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Progression-Free Survival (PFS) in the First-Line Subpopulation | The criteria for PD are identified in previous outcome measure(s). PFS was defined as the time from the first dose of trial treatment to the first documentation of PD or death, whichever occurred first. PFS was calculated in months as [first event date minus first dose date plus 1] divided by 30.44. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants With Tumor Response of CR or CRi Experiencing PD or Death in the First-Line Subpopulation | The criteria for CR, CRi, and PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Disease-Free Survival (DFS) in the First-Line Subpopulation | The criteria for CR, CRi, and PD are identified in previous outcome measure(s). DFS was defined as the time from the first assessment of CR or CRi to the first documentation of PD or death, whichever occurred first. DFS was calculated in months as [first event date minus first assessment date of CR/CRi plus 1] divided by 30.44. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants Experiencing PD, Documented Intake of New Leukemia Therapy, or Death in the First-Line Subpopulation | The criteria for PD are identified in previous outcome measure(s). The percentage of participants experiencing PD, intake of new (post-trial) leukemia therapy, or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Event-Free Survival (EFS) in the First-Line Subpopulation | The criteria for PD and SD are identified in previous outcome measure(s). EFS was defined as the time from the first dose of trial treatment to the first documentation of PD, the beginning of new treatment for any hematologic malignancy, or death from any cause. Those with SD were considered event-free. EFS was calculated in months as [first event date minus first dose date plus 1] divided by 30.44. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants With Documented Intake of New Leukemia Therapy in the First-Line Subpopulation | The percentage of participants with documented intake of new (post-trial) leukemia therapy was calculated as the number of participants with new therapy divided by the number of participants analyzed, multiplied by 100. | During Cycles 1 to 6 (both treatment arms), Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Time to Next Leukemia Treatment (TNLT) in the First-Line Subpopulation | TNLT was defined as the time from the first dose of trial treatment to the first documentation of any new leukemia treatment. TNLT was calculated in months as [first new treatment date minus first dose date plus 1] divided by 30.44. | During Cycles 1 to 6 (both treatment arms), Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants With Tumor Response of CR, CRi, PR, or nPR Experiencing PD or Death in the First-Line Subpopulation | The criteria for CR, CRi, PR, nPR, and PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Duration of Response in the First-Line Subpopulation | The criteria for CR, CRi, PR, nPR, and PD are identified in previous outcome measure(s). Duration of response was defined as the time from the first assessment of CR, CRi, PR, or nPR to the first documentation of PD or death, whichever occurred first. Duration of response was calculated in months as [first event date minus first assessment date of CR/CRi/PR/nPR plus 1] divided by 30.44. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants Experiencing Death in the First-Line Subpopulation | The percentage of participants experiencing death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Overall Survival (OS) in the First-Line Subpopulation | OS was defined as the time from recorded diagnosis to death from any cause. OS was calculated in months as [death date or last-known alive date minus diagnosis date plus 1] divided by 30.44. | End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years) | 
| Percentage of Participants Achieving Molecular Response in the First-Line Subpopulation | Molecular response was defined as negative minimal residual disease (MRD) during study treatment or within 4 months after the end of treatment. Negative MRD was defined as a proportion of malignant B-cells in normal B-cells < 0.0001. The percentage of participants achieving molecular response was calculated as the number of participants with negative MRD divided by the number of participants analyzed. | Up to 4 months after the last treatment cycle (up to 40 weeks) | 
| Number of Participants With Positive and Negative Outcome for MRD in the First-Line Subpopulation | Negative MRD was defined as a proportion of malignant B-cells in normal B-cells < 0.0001, and positive MRD was defined as a proportion of malignant B-cells in normal B-cells >/= 0.0001. | After 6 treatment cycles (up to 24 weeks) | 
| Proportion of Malignant B-cells in Normal B-cells Among Participants With a Positive Outcome for MRD in the First-Line Subpopulation | The proportion of malignant B-cells in normal B-cells was quantitatively determined, and was calculated as the number of malignant B-cells divided by the number of normal B-cells observed. | After 6 treatment cycles (up to 24 weeks) |