A Study to Assess the Efficacy of Rituximab (MabThera) in First Line Treatment of Chronic Lymphocytic Leukemia (CLL)
- Conditions
- Leukemia, Lymphocytic, Chronic, B-Cell
- Interventions
- Registration Number
- NCT00545714
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 86
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Rituximab + Fludarabine + Cyclophosphamide Cyclophosphamide 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. Rituximab + Fludarabine + Cyclophosphamide Rituximab 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. Rituximab + Fludarabine + Cyclophosphamide Fludarabine 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen Month 9 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry 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 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.
Percentage of Participants With Clinical Response of CR or PR Among Participants With Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry 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 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.
Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi) Baseline up to progressive disease (PD) or death due to any cause, whichever occurred first (up to 92 months) 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.
Percentage of Participants Who Died Baseline up to death due to any cause (up to 92 months) Overall Survival (OS) Baseline up to death due to any cause (up to 92 months) 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.
Percentage of Participants With PD or Death Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) 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.
Progression-Free Survival (PFS) Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) 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.
Treatment-Free Survival (TFS) Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months) 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.
Duration of Response (DOR) From first CR or PR up to detectable MRD or disease occurrence/PD, whichever occurred first (up to 92 months) 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.
Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood 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 Percentages of participants with CD38 expression by \>/=30% of CLL cells during the Induction Phase, Maintenance Phase, and Follow-Up were reported.
Percentage of Participants With Genetic Abnormalities Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months) 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.
Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression 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 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.
Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement 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 Percentages of participants with IgH rearrangement during the Induction Phase, Maintenance Phase, and Follow-Up were reported.
Trial Locations
- Locations (33)
Hospital Clinico Universitario Lozano Blesa; Servicio de Hematologia
🇪🇸Zaragoza, Spain
Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
🇪🇸Salamanca, Spain
Hospital Universitario Puerta del Mar; Servicio de Hematologia
🇪🇸Cádiz, Cadiz, Spain
Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia
🇪🇸Valencia, Spain
Hospital Universitario la Fe; Servicio de Hematologia
🇪🇸Valencia, Spain
Hospital General Universitario de Valencia; Servicio de Hematologia
🇪🇸Valencia, Spain
Hospital Universitario Dr. Peset; Servicio de Hematologia
🇪🇸Valencia, Spain
Hospital Universitario Miguel Servet; Servicio Hematologia
🇪🇸Zaragoza, Spain
Hospital De Txagorritxu; Servicio de Hematologia
🇪🇸Vitoria, Alava, Spain
Hospital de Jerez de la Frontera; Servicio de Hematologia
🇪🇸Jerez de La Frontera, Cadiz, Spain
Hospital Universitario Marques de Valdecilla; Servicio de Hematologia
🇪🇸Santander, Cantabria, Spain
Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Hematologia
🇪🇸La Coruna, LA Coruña, Spain
Fundacion Hospital de Alcorcon; Servicio de Hematologia
🇪🇸Alcorcon, Madrid, Spain
Hosital Universitario de Mostoles;Servicio de Hematologia
🇪🇸Mostoles, Madrid, Spain
Hospital Francesc de Borja; Servicio de Hematologia
🇪🇸Gandia, Valencia, Spain
Hospital Universitario Infanta Cristina; Servicio de Hematologia
🇪🇸Badajoz, Spain
Hospital de Sagunto; Servicio de Hematologia
🇪🇸Sagunto, Valencia, Spain
Hospital de Basurto; Servicio de Hematologia
🇪🇸Bilbao, Vizcaya, Spain
Hospital San Pedro De Alcantara; Servicio de Hematologia
🇪🇸Caceres, Spain
Hospital General de Castellon; Servicio de Hematologia
🇪🇸Castellon, Spain
Hospital Duran i Reynals; Servicio de Hematologia
🇪🇸Barcelona, Spain
Hospital Universitario Virgen de las Nieves; Servicio de Hematologia
🇪🇸Granada, Spain
Hospital Ramon y Cajal; Servicio de Hematologia
🇪🇸Madrid, Spain
Hospital General Universitario Gregorio Marañon; Servicio de Hematología
🇪🇸Madrid, Spain
Hospital Univ. 12 de Octubre; Servicio de Hematologia
🇪🇸Madrid, Spain
Hospital Universitario Clínico San Carlos; Servicio de Hematología
🇪🇸Madrid, Spain
Hospital Universitario la Paz; Servicio de Hematologia
🇪🇸Madrid, Spain
HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia
🇪🇸Madrid, Spain
Hospital Universitario Puerta de Hierro; Servicio de Hematologia
🇪🇸Madrid, Spain
Hospital Universitario Principe de Asturias; Servicio de Hematología
🇪🇸Madrid, Spain
Hospital General Universitario J.M Morales Meseguer; Servicio de Hematología
🇪🇸Murcia, Spain
Hospital Universitario de Getafe; Servico de Hematologia
🇪🇸Madrid, Spain
Hospital Clinico Universitario Virgen de la Victoria; Servicio de Hematologia
🇪🇸Malaga, Spain