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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01056510
First received: January 25, 2010
Last updated: June 24, 2015
Last verified: June 2015
  Purpose

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.


Condition Intervention Phase
Lymphocytic Leukemia, Chronic
Drug: bendamustine
Drug: chlorambucil
Drug: rituximab [MabThera/Rituxan]
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 [ Time Frame: At least 2 months after completion of therapy (up to 32 weeks) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Pooled Population After 6 Cycles of Therapy [ Time Frame: At least 2 months after completion of therapy (up to 32 weeks) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Second-Line Subpopulation After 6 Cycles of Therapy [ Time Frame: At least 2 months after completion of therapy (up to 32 weeks) ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants by Disease Response Category in the First-Line Subpopulation [ Time Frame: After 6 treatment cycles and at the confirmation of response assessment at least 12 weeks later (up to 36 weeks) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Experiencing PD or Death in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Progression-Free Survival (PFS) in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Tumor Response of CR or CRi Experiencing PD or Death in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Disease-Free Survival (DFS) in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Experiencing PD, Documented Intake of New Leukemia Therapy, or Death in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Event-Free Survival (EFS) in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Documented Intake of New Leukemia Therapy in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Time to Next Leukemia Treatment (TNLT) in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Tumor Response of CR, CRi, PR, or nPR Experiencing PD or Death in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Duration of Response in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Experiencing Death in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) in the First-Line Subpopulation [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Achieving Molecular Response in the First-Line Subpopulation [ Time Frame: Up to 4 months after the last treatment cycle (up to 40 weeks) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Positive and Negative Outcome for MRD in the First-Line Subpopulation [ Time Frame: After 6 treatment cycles (up to 24 weeks) ] [ Designated as safety issue: No ]
    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.

  • Proportion of Malignant B-cells in Normal B-cells Among Participants With a Positive Outcome for MRD in the First-Line Subpopulation [ Time Frame: After 6 treatment cycles (up to 24 weeks) ] [ Designated as safety issue: No ]
    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.


Enrollment: 357
Study Start Date: March 2010
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A Drug: bendamustine
90mg/m2 (first-line) or 70mg/m2 (second-line) iv, days 1 and 2 every 4 weeks, cycles 1-6
Drug: rituximab [MabThera/Rituxan]
375mg/m2 iv day 1 of cycle 1, followed by 500mg/m2 iv every 4 weeks cycles 2-6
Experimental: B Drug: chlorambucil
10mg/m2 po days 1-7 every 4 weeks, for up to 12 cycles
Drug: rituximab [MabThera/Rituxan]
375mg/m2 iv day 1 of cycle 1, followed by 500mg/m2 iv every 4 weeks cycles 2-6

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01056510

  Show 85 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01056510     History of Changes
Other Study ID Numbers: MO22468, 2009-012072-28
Study First Received: January 25, 2010
Results First Received: June 2, 2015
Last Updated: June 24, 2015
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Bendamustine
Chlorambucil
Rituximab
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on July 01, 2015