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A Study to Assess the Effect of Maintenance Treatment With Rituximab Versus No Treatment in Participants With Progressive B-Cell Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT00718549
Recruitment Status : Completed
First Posted : July 18, 2008
Results First Posted : August 20, 2018
Last Update Posted : August 20, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

July 16, 2008
July 18, 2008
May 31, 2017
August 20, 2018
August 20, 2018
July 21, 2009
September 14, 2015   (Final data collection date for primary outcome measure)
  • Percentage of Participants With Disease Progression (PD), Relapse, or Death Due to Any Cause Assessed According to the National Cancer Institute (NCI) Revised Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) [ Time Frame: From randomization to PD, Relapse, or death due to any cause (overall approximately 5 years) ]
    PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (greater than [>]1.5 centimeters [cm]), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of greater than or equal to (>/=) 50 percent (%) in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000 per microliter (/mcL); transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
  • Progression-Fee Survival (PFS) Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL [ Time Frame: From randomization to PD, relapse, or death due to any cause (overall approximately 5 years) ]
    PFS was defined as the time from date of randomization to date of PD, relapse, or death due to any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Progression-free survival in the maintenance phase [ Time Frame: Event driven ]
Complete list of historical versions of study NCT00718549 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL [ Time Frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129) ]
    CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, platelets (PL) >100,000/mcL, hemoglobin (Hb) >11.0 grams per deciliter (g/dL), bone marrow (BM) sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly (decrease in lymph node size by >/=50% compared to pre-treatment state, no increase in any lymph node, no new enlarged lymph node); a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).
  • Percentage of Participants With Minimal Residual Disease (MRD) According to Rawstron Criteria in Participants With CR or PR [ Time Frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129) ]
    MRD was defined by the presence of tumor cells in bone marrow, using 4-color flow cytometry of cluster of differentiation (CD)19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR: if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).
  • PFS Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors [ Time Frame: From randomization to PD, relapse, or death due to any cause (overall approximately 5 years) ]
    PFS: time from date of randomization to date of PD, relapse, or death from any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in previously noted enlargement of liver or spleen by >/=50%; an increase in number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and clinical outcome (PFS) after study treatment.
  • Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 29 [ Time Frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) ]
    CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
  • Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 129 [ Time Frame: 12 weeks after the end of maintenance treatment or observation phase (Week 129) ]
    CR was achieved if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
  • Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 29 [ Time Frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) ]
    MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
  • Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 129 [ Time Frame: 12 weeks after the end of maintenance treatment or observation phase (Week 129) ]
    MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
Complete response and partial response in induction phase [ Time Frame: Event driven ]
Not Provided
Not Provided
 
A Study to Assess the Effect of Maintenance Treatment With Rituximab Versus No Treatment in Participants With Progressive B-Cell Chronic Lymphocytic Leukemia (CLL)
A Randomized, Open Label Study to Assess the Effect of Maintenance Treatment With Mabthera (Rituximab) Versus No Treatment, After Induction Treatment With Rituximab, Cladribine and Cyclophosphamide (RCC) on Progression-Free Survival in Previously Untreated Patients With Progressive B-Cell Chronic Lymphocytic Leukemia
This study will assess the effect of maintenance treatment with rituximab in comparison with observation period (no treatment), in participants with progressive B-cell CLL who have had previous first-line induction treatment with rituximab, cladribine and cyclophosphamide (RCC regimen). After 6 months of RCC induction therapy, participants will be randomized either to receive maintenance treatment with rituximab or to receive no treatment (observation only) for 96 weeks. Participants completing maintenance/observation period will be followed-up for approximately 3 years.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Lymphocytic Leukemia, Chronic
  • Drug: Cladribine
    Cladribine will be adminiatered at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4 of each 28-day cycle during induction phase.
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administred at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 of each 28-day cycle during induction phase.
  • Drug: Rituximab
    Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 during induction phase. Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle during maintenance phase.
    Other Name: MabThera
  • Experimental: Induction: Rituximab, Cladribine, Cyclophosphamide
    Participants will receive rituximab at a dose of 375 milligrams per meter squared (mg/m^2) as intravenous (IV) infusion on Day 1, cladribine at a dose of 0.12 milligrams per kilogram per day (mg/kg/day) as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 will be administered in Cycles 2-6. Each cycle will be of 28 days in duration.
    Interventions:
    • Drug: Cladribine
    • Drug: Cyclophosphamide
    • Drug: Rituximab
  • Experimental: Maintenance Arm: Rituximab
    Participants with PR or CR after induction phase who will be randomized to maintenance arm will receive rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants will receive rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).
    Intervention: Drug: Rituximab
  • No Intervention: Observation Arm: No Intervention
    Participants with PR or CR after induction phase who will be randomized to observation arm will not receive any intervention. Participants will be assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
128
200
September 14, 2015
September 14, 2015   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Immunologically confirmed diagnosis of B-cell CLL
  • Rai stage I-IV disease with evidence of progression
  • No previous chemotherapy, radiotherapy, or immunotherapy for B-cell CLL
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

  • Active secondary malignancy or transformation to aggressive lymphoma
  • Medical condition requiring chronic use of oral corticosteroids at a dose of 1 mg/kg or 60 mg/m^2 over 2 weeks
  • Prior treatment with interferon, rituximab or another monoclonal antibody, immunosuppressive treatment or radiotherapy before inclusion to the study
  • History of other malignancies within 2 years before study entry, except for dequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Belarus,   Poland
 
 
NCT00718549
ML21283
2008-001140-39
Yes
Not Provided
Not Provided
Hoffmann-La Roche
Hoffmann-La Roche
Not Provided
Study Director: Clinical Trials Hoffmann-La Roche
Hoffmann-La Roche
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP