A Study to Assess the Efficacy of Rituximab (MabThera) in First Line Treatment of Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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This single arm study will assess the efficacy and safety of rituximab in combination with fludarabine and cyclophosphamide, followed by rituximab maintenance therapy, as first line treatment of participants with CLL.

Official Title
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Multicentre, Non-Randomised, Open-Label Phase II Study to Evaluate the Efficacy and Safety of Induction Treatment With Rituximab, Fludarabine, Cyclophosphamide, Followed by Rituximab Maintenance Therapy (R-Fc-Rm) in the First Line Treatment of Chronic Lymphocytic Leukaemia

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CLL according to World Health Organization diagnostic criteria Active disease No previous treatment Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Exclusion Criteria: Transformation to aggressive B-cell malignancy (prolymphocytic leukemia, large-cell lymphoma, Hodgkin's lymphoma) Other malignancies except for localized skin cancer Continuous systemic corticosteroid treatment Known infection with hepatitis B or C

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab + Fludarabine + Cyclophosphamide<br>Participants will receive 6 cycles (cycle length = 28 days) of treatment with rituximab (375 milligrams per square meter [mg/m^2] as intravenous [IV] infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6); fludarabine (25 mg/m^2 on Days 1-3) and cyclophosphamide (250 mg/m^2 on Days 1-3). Participants with a partial or complete response and appropriate neutrophil conditions will receive maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6. | Drug: Cyclophosphamide<br>* Cyclophosphamide 250 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.<br>Drug: Fludarabine<br>* Fludarabine 25 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.<br>Drug: Rituximab<br>* Rituximab 375 mg/m^2 as IV infusion will be administered on Day 0 of Cycle 1; 500 mg/m^2 as IV infusion will be administered on Day 1 of Cycle 2-6; and 375 mg/m^2 as IV infusion every 2 months from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6.<br>* Other names: MabThera, Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen | CR was defined as no adenopathies (ADPs) and visceromegalies (VSMs) in physical examination (PE); no general symptoms (Sx); lymphocytes (Lymph) in peripheral blood less than (<) 4000 per cubic millimeter (mm^3); normalization of peripheral blood parameters: neutrophils (Neut) greater than (>) 1500/mm^3, platelets (Plt) >100,000/mm^3, hemoglobin (Hb) >11 grams per deciliter (g/dL) without transfusion; normocellular bone marrow (BM) with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. | Month 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry | CR was defined as no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR was defined as decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. | Post-Induction Phase (IP): at 6 months; during Maintenance Phase (MP): at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up (FU): at Follow-Up Months 6, 12, 18, 24, 30, 36 | 
| Percentage of Participants With Clinical Response of CR or PR Among Participants With Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry | CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR: decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. Negative MRD: Lymph <0.01% of all white blood cells (WBCs) in blood or BM after two consecutive measurements. Analysis performed only in blood during the Maintenance Phase and Follow-Up. | Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 36 | 
| Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi) | Participants with CRi were those who met all CR criteria (including BM examinations) but had persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to chronic lymphocytic leukemia (CLL) but related to drug toxicity. CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. | Baseline up to progressive disease (PD) or death due to any cause, whichever occurred first (up to 92 months) | 
| Percentage of Participants Who Died |  | Baseline up to death due to any cause (up to 92 months) | 
| Overall Survival (OS) | OS was defined as time from treatment start to death of the participant. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered. OS was estimated using Kaplan-Meier (KM) methodology. | Baseline up to death due to any cause (up to 92 months) | 
| Percentage of Participants With PD or Death | PD was defined as new ADPs (1.5 centimeters [cm]), hepato-/splenomegaly (HSM), Richter syndrome (RS), or other infiltrated organs; greater than or equal to (>/=) 50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. | Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) | 
| Progression-Free Survival (PFS) | PFS was defined as time from start of study treatment to PD or death, whichever occurred first. For other participants, last follow-up available was taken as last control. If participant did not complete study, date of last visit available was considered. PFS was estimated using KM methodology. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. | Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) | 
| Treatment-Free Survival (TFS) | TFS was defined time from start of study treatment until participant received new chemotherapy/immunotherapy because of PD and to reduce the disease with palliative or curative intent. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells. | Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) | 
| Duration of Response (DOR) | DOR: time from CR/PR to MRD/PD. PD: new ADP (1.5 cm), HSM, RS, other infiltrated organs or >/=50% increase size in those with PR; blood Lymph increase >/=50% with B Lymph >/=5000/mm^3; cytopenia due to CLL. Progression of (nonautoimmune) cytopenia: 2-g/dL decrease basal Hb, Hb <10 g/dL, >/=50% decrease basal Plt or <100,000/mm^3 at >/=3 months post-treatment was PD if clonal CLL cell infiltration on BM biopsy. CR: no ADP/VSM in PE; no general Sx; blood Lymph <4000/mm^3; Neut >1500/mm^3; Plt >100,000/mm^3; Hb >11 g/dL (no transfusion); normocellular BM with <30% Lymph; BM aspirate/biopsy with no lymphoid nodule infiltration. PR: >50% decrease blood Lymph; >50% decrease in total sum up to 6 ADPs or baseline ADP of LD, no new/enlargement of prior ADP; >50% decrease VSM; Neut >1500/mm^3 or >50% increase; Plt >100,000/mm^3 or >50% increase; Hb >11.0 g/dL or >50% increase (no transfusion). All CR criteria but persistent anemia or thrombocytopenia was PR. MRD: Lymph >0.01% of blood/BM WBCs. | From first CR or PR up to detectable MRD or disease occurrence/PD, whichever occurred first (up to 92 months) | 
| Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood | Percentages of participants with CD38 expression by >/=30% of CLL cells during the Induction Phase, Maintenance Phase, and Follow-Up were reported. | Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36 | 
| Percentage of Participants With Genetic Abnormalities | Percentages of participants with genetic abnormalities (deletion 6q, deletion 11q22-q23, deletion p53, trisomy 12, and deletion 13q14) in the course of the disease during the Induction Phase and Maintenance Phase were reported. | Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months) | 
| Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression | Percentages of participants with positive and negative ZAP-70 expression during the Induction Phase, Maintenance Phase, and Follow-Up were reported. Positive ZAP-70 was defined as ZAP-70 expression by >/=20% of CLL cells. Negative ZAP-70 was defined as ZAP-70 expression by <20% of CLL cells. | Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36 | 
| Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement | Percentages of participants with IgH rearrangement during the Induction Phase, Maintenance Phase, and Follow-Up were reported. | Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36 |