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

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

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.

Study Overview

• Status: Completed
• Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Rituximab

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: MabThera, Rituxan

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Garcia-Marco JA, Jimenez JL, Recasens V, Zarzoso MF, Gonzalez-Barca E, De Marcos NS, Ramirez MJ, Parraga FJP, Yanez L, De La Serna Torroba J, Malo MDG, Ariznavarreta GD, Persona EP, Guinaldo MAR, De Paz Arias R, Llanos EB, Jarque I, Valle MDCF, Tatay AC, De Oteyza JP, Martin EMD, Fernandez IP, Martinez RM, Costa MAA, Champ D, Suarez JG, Diaz MG, Ferrer S, Carbonell F, Garcia-Vela JA; GELLC Study Group. High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance. Haematologica. 2019 Nov;104(11):2249-2257. doi: 10.3324/haematol.2018.204891. Epub 2019 Mar 19.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2007
• Primary Completion (Actual): May 20, 2016
• Study Completion (Actual): May 20, 2016

Study Registration Dates

• First Submitted: October 16, 2007
• First Submitted That Met QC Criteria: October 16, 2007
• First Posted (Estimate): October 17, 2007

Study Record Updates

• Last Update Posted (Actual): January 16, 2019
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Rituximab; Fludarabine
• Other Study ID Numbers: ML21135; 2007-002733-36 (EudraCT Number)