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

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ClinicalTrials.gov Identifier: NCT00545714
Recruitment Status : Completed
First Posted : October 17, 2007
Results First Posted : January 16, 2019
Last Update Posted : January 16, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Drug: Cyclophosphamide Drug: Fludarabine Drug: Rituximab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 86 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 21, 2007
Actual Primary Completion Date : May 20, 2016
Actual Study Completion Date : May 20, 2016


Arm Intervention/treatment
Experimental: Rituximab + Fludarabine + 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.
Drug: Cyclophosphamide
Cyclophosphamide 250 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.

Drug: Fludarabine
Fludarabine 25 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.

Drug: Rituximab
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.
Other Name: MabThera, Rituxan




Primary Outcome Measures :
  1. Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen [ Time Frame: 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 :
  1. Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry [ Time Frame: 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.

  2. Percentage of Participants With Clinical Response of CR or PR Among Participants With Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry [ Time Frame: 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.

  3. Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi) [ Time Frame: 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.

  4. Percentage of Participants Who Died [ Time Frame: Baseline up to death due to any cause (up to 92 months) ]
  5. Overall Survival (OS) [ Time Frame: 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.

  6. Percentage of Participants With PD or Death [ Time Frame: 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.

  7. Progression-Free Survival (PFS) [ Time Frame: 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.

  8. Treatment-Free Survival (TFS) [ Time Frame: 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.

  9. Duration of Response (DOR) [ Time Frame: 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.

  10. Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood [ Time Frame: 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.

  11. Percentage of Participants With Genetic Abnormalities [ Time Frame: 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.

  12. Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression [ Time Frame: 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.

  13. Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00545714


Locations
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Spain
Hospital De Txagorritxu; Servicio de Hematologia
Vitoria, Alava, Spain, 01009
Hospital Universitario Puerta del Mar; Servicio de Hematologia
Cádiz, Cadiz, Spain, 11009
Hospital de Jerez de la Frontera; Servicio de Hematologia
Jerez de La Frontera, Cadiz, Spain, 11407
Hospital Universitario Marques de Valdecilla; Servicio de Hematologia
Santander, Cantabria, Spain, 39008
Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Hematologia
La Coruna, LA Coruña, Spain, 15006
Fundacion Hospital de Alcorcon; Servicio de Hematologia
Alcorcon, Madrid, Spain, 28922
Hosital Universitario de Mostoles;Servicio de Hematologia
Mostoles, Madrid, Spain, 28935
Hospital Francesc de Borja; Servicio de Hematologia
Gandia, Valencia, Spain, 46702
Hospital de Sagunto; Servicio de Hematologia
Sagunto, Valencia, Spain, 46520
Hospital de Basurto; Servicio de Hematologia
Bilbao, Vizcaya, Spain, 48013
Hospital Universitario Infanta Cristina; Servicio de Hematologia
Badajoz, Spain, 06080
Hospital Duran i Reynals; Servicio de Hematologia
Barcelona, Spain, 08907
Hospital San Pedro De Alcantara; Servicio de Hematologia
Caceres, Spain, 10003
Hospital General de Castellon; Servicio de Hematologia
Castellon, Spain, 12004
Hospital Universitario Virgen de las Nieves; Servicio de Hematologia
Granada, Spain, 18014
Hospital General Universitario Gregorio Marañon; Servicio de Hematología
Madrid, Spain, 28007
Hospital Ramon y Cajal; Servicio de Hematologia
Madrid, Spain, 28034
Hospital Universitario Clínico San Carlos; Servicio de Hematología
Madrid, Spain, 28040
Hospital Univ. 12 de Octubre; Servicio de Hematologia
Madrid, Spain, 28041
Hospital Universitario la Paz; Servicio de Hematologia
Madrid, Spain, 28046
HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia
Madrid, Spain, 28050
Hospital Universitario Puerta de Hierro; Servicio de Hematologia
Madrid, Spain, 28222
Hospital Universitario Principe de Asturias; Servicio de Hematología
Madrid, Spain, 28805
Hospital Universitario de Getafe; Servico de Hematologia
Madrid, Spain, 28905
Hospital Clinico Universitario Virgen de la Victoria; Servicio de Hematologia
Malaga, Spain, 29010
Hospital General Universitario J.M Morales Meseguer; Servicio de Hematología
Murcia, Spain, 30008
Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
Salamanca, Spain, 37007
Hospital General Universitario de Valencia; Servicio de Hematologia
Valencia, Spain, 46014
Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia
Valencia, Spain, 46015
Hospital Universitario Dr. Peset; Servicio de Hematologia
Valencia, Spain, 46017
Hospital Universitario la Fe; Servicio de Hematologia
Valencia, Spain, 46026
Hospital Clinico Universitario Lozano Blesa; Servicio de Hematologia
Zaragoza, Spain, 50009
Hospital Universitario Miguel Servet; Servicio Hematologia
Zaragoza, Spain, 50009
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00545714     History of Changes
Other Study ID Numbers: ML21135
2007-002733-36 ( EudraCT Number )
First Posted: October 17, 2007    Key Record Dates
Results First Posted: January 16, 2019
Last Update Posted: January 16, 2019
Last Verified: July 2018
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Vidarabine
Cyclophosphamide
Rituximab
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents