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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00738374
First received: August 18, 2008
Last updated: February 12, 2015
Last verified: February 2015
  Purpose
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.

Condition Intervention Phase
Lymphocytic Leukemia, Chronic
Drug: rituximab [MabThera/Rituxan]
Drug: chlorambucil
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Documented CR, CRi, or PR at the End of Induction Treatment [ Time Frame: Month 10 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Percentage of Participants With Documented CR, CRi, or PR at the End of Study [ Time Frame: Month 35 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 10 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 35 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 10 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 35 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 35 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 35 ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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) [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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.


Enrollment: 97
Study Start Date: November 2008
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: rituximab [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).
Drug: chlorambucil
8mg/m2 po on days 1-7 of courses 1-8

  Eligibility

Ages Eligible for Study:   60 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT00738374

Locations
Italy
Catanzaro, Calabria, Italy, 88100
Cosenza, Calabria, Italy, 87100
Reggio Calabria, Calabria, Italy, 89100
Napoli, Campania, Italy, 80131
Bologna, Emilia-Romagna, Italy, 40138
Ferrara, Emilia-Romagna, Italy, 44100
Roma, Lazio, Italy, 00144
Roma, Lazio, Italy, 00161
Genova, Liguria, Italy, 16132
Milano, Lombardia, Italy, 20122
Milano, Lombardia, Italy, 20162
Torino, Piemonte, Italy, 10126
Bari, Puglia, Italy, 70124
Catania, Sicilia, Italy, 95124
Messina, Sicilia, Italy, 98165
Firenze, Toscana, Italy, 50135
Siena, Toscana, Italy, 53100
Padova, Veneto, Italy, 35128
Verona, Veneto, Italy, 37134
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00738374     History of Changes
Other Study ID Numbers: ML21445  2008-001612-20 
Study First Received: August 18, 2008
Results First Received: December 19, 2014
Last Updated: February 12, 2015
Health Authority: Italy: Ministry of Health

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

ClinicalTrials.gov processed this record on August 23, 2016