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

Leukemia, Lymphocytic, Chronic, B-Cell Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00545714
• Other study ID #: ML21135
• Secondary ID: 2007-002733-36
• Status: Completed
• Phase: Phase 2
• Start date: November 21, 2007
• Est. completion date: May 20, 2016

Study information

• Verified date: July 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: May 20, 2016
• Est. primary completion date: May 20, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide 250 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.
• Fludarabine
Fludarabine 25 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.
• 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.

Locations

Country	Name	City	State
Spain	Fundacion Hospital de Alcorcon; Servicio de Hematologia	Alcorcon	Madrid
Spain	Hospital Universitario Infanta Cristina; Servicio de Hematologia	Badajoz
Spain	Hospital Duran i Reynals; Servicio de Hematologia	Barcelona
Spain	Hospital de Basurto; Servicio de Hematologia	Bilbao	Vizcaya
Spain	Hospital San Pedro De Alcantara; Servicio de Hematologia	Caceres
Spain	Hospital Universitario Puerta del Mar; Servicio de Hematologia	Cádiz	Cadiz
Spain	Hospital General de Castellon; Servicio de Hematologia	Castellon
Spain	Hospital Francesc de Borja; Servicio de Hematologia	Gandia	Valencia
Spain	Hospital Universitario Virgen de las Nieves; Servicio de Hematologia	Granada
Spain	Hospital de Jerez de la Frontera; Servicio de Hematologia	Jerez de La Frontera	Cadiz
Spain	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Hematologia	La Coruna	LA Coruña
Spain	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia	Madrid
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Hematología	Madrid
Spain	Hospital Ramon y Cajal; Servicio de Hematologia	Madrid
Spain	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Clínico San Carlos; Servicio de Hematología	Madrid
Spain	Hospital Universitario de Getafe; Servico de Hematologia	Madrid
Spain	Hospital Universitario la Paz; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Principe de Asturias; Servicio de Hematología	Madrid
Spain	Hospital Universitario Puerta de Hierro; Servicio de Hematologia	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Hematologia	Malaga
Spain	Hosital Universitario de Mostoles;Servicio de Hematologia	Mostoles	Madrid
Spain	Hospital General Universitario J.M Morales Meseguer; Servicio de Hematología	Murcia
Spain	Hospital de Sagunto; Servicio de Hematologia	Sagunto	Valencia
Spain	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca
Spain	Hospital Universitario Marques de Valdecilla; Servicio de Hematologia	Santander	Cantabria
Spain	Hospital Arnau de Vilanova (Valencia) 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 la Fe; Servicio de Hematologia	Valencia
Spain	Hospital De Txagorritxu; Servicio de Hematologia	Vitoria	Alava
Spain	Hospital Clinico Universitario Lozano Blesa; Servicio de Hematologia	Zaragoza
Spain	Hospital Universitario Miguel Servet; Servicio Hematologia	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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)
Secondary	Percentage of Participants Who Died		Baseline up to death due to any cause (up to 92 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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