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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lymphocytic Leukemia, Chronic

Intervention / Treatment
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* Drug: Cladribine
* Drug: Cyclophosphamide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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

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: Induction: Rituximab, Cladribine, Cyclophosphamide<br>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. | Drug: Cladribine<br>* 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.<br>Drug: Cyclophosphamide<br>* 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.<br>Drug: Rituximab<br>* 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.<br>* Other names: MabThera;|
| Experimental: Maintenance Arm: Rituximab<br>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). | Drug: Rituximab<br>* 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.<br>* Other names: MabThera;|
| No Intervention: Observation Arm: No Intervention<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | From randomization to PD, Relapse, or death due to any cause (overall approximately 5 years) | 
| Progression-Fee Survival (PFS) Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL | 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. | From randomization to PD, relapse, or death due to any cause (overall approximately 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL | 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). | 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) | 
| Percentage of Participants With Minimal Residual Disease (MRD) According to Rawstron Criteria in Participants With CR or PR | 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). | 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) | 
| PFS Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors | 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. | From randomization to PD, relapse, or death due to any cause (overall approximately 5 years) | 
| 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 | 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. | 8 weeks after the last dose of rituximab during induction treatment (Week 29) | 
| 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 | 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. | 12 weeks after the end of maintenance treatment or observation phase (Week 129) | 
| Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at 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. | 8 weeks after the last dose of rituximab during induction treatment (Week 29) | 
| Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at 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. | 12 weeks after the end of maintenance treatment or observation phase (Week 129) |