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

Lymphocytic Leukemia, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00738374
• Other study ID #: ML21445
• Secondary ID: 2008-001612-20
• Status: Completed
• Phase: Phase 2
• First received: August 18, 2008
• Last updated: February 12, 2015
• Start date: November 2008
• Est. completion date: January 2013

Study information

• Verified date: February 2015
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 97
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphocytic Leukemia, Chronic

Intervention

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).
• chlorambucil
8mg/m2 po on days 1-7 of courses 1-8

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Month 10	No
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.	Month 35	No
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.	Month 10	No
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.	Month 35	No
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.	Month 10	No
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.	Month 35	No
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.	Month 35	No
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.	Month 35	No
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.	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.	No
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.	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.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No
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.	Screening, Day 1 Courses 1-8 (4-week courses) and Day 1 of Courses 10-35 (4-week courses) for up to 35 months.	No