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Intensified Rituimab Prephase Before FCR in Untreated B-CLL

Primary Purpose

B-cell Chronic Lymphocytic Leukemia CLL

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Rituximab
Rituximab
Cyclophosphamide
Fludarabine
Sponsored by
French Innovative Leukemia Organisation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia CLL focused on measuring B CLL, Fist line treatment

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Patient information and written informed consent
  • 18 years < Age < 66 ans
  • confirmed B-CLL Matutes score 4 or 5
  • Binet stage C or Binet stage A and B with active disease could be considered for inclusion. For stage A with active disease an agreement of investigator coordinator is required.
  • no prior treatment except steroids for less than 1 month (detail corticoid)
  • No 17p deletion as assessed by FISH < 10 % positive nuclei
  • Performance status ECOG < 2
  • CIRS Cumulative Illness Rating Scale < 6

Exclusion criteria:

  • Binet stage A without active disease according to IWCLL 2008 criteria
  • Know HIV seropositivity
  • Hepatitis B or C seropositivity unless clearly due to vaccination
  • Life expectancy < 6 months
  • Clinically significant auto-immune anemia
  • Active second malignancy currently requiring treatment (except basal cell carcinoma in situ endometrial carcinoma and incidental prostate carcinoma) and/or less than 5 years CR after breast cancer
  • Any severe co-morbid conditions such as Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarythmias requiring ongoing treatment, severe chronic obstructive pulmonary disease with hypoxemia, uncontrolled diabetes mellitus, or uncontrolled hypertension
  • Concomitant disease requiring prolonged use of corticosteroids > 1 month
  • Known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs According to the SmPC or investigator practice
  • Contraindication to use of Rituximab
  • Transformation to aggressive B-cell malignancy e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukaemia
  • Active bacterial, viral or fungal infection
  • Abnormal renal function with creatinine clearance < 60 ml/min calculated according to the Cockcroft and Gault formula
  • Total bilirubin, gamma glutamyltransferase or transaminase levels > 2.5 ULN.
  • Any coexisting medical or psychological condition that would preclude participation in the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment.
  • Pregnant or breastfeeding women.
  • Adult under law-control
  • Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study.
  • No afiliate to social security

Sites / Locations

  • Stephane LEPRETRE
  • Guillaume CARTRON

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard R-FC arm

DenseR-FC arm

Arm Description

Standard R-FC arm 6 cycles every 28 days Cycle 1: Rituximab : 375 mg/m² i.v on day 1 Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days For patients with Leucocyte count > 25* G/L : rituximab in two equal doses at D1, D2 Cycle 2-6: Rituximab: 500 mg/m² i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days

DenseR-FC arm =1 prephase R Dense course +6 R-FC courses Prephase: - Rituximab: 500 mg on day 0, 2000 mg on days 1, 8, and D15 For patients with Leucocyte count > 25* G/L : rituximab 250 mg D-1, D0 prephase Cycle 1-6 (cycle 1 beginning at D22): Rituximab: 500 mg/m2 i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days

Outcomes

Primary Outcome Measures

complete response rates according to IWCLL 2008 guidelines with undetectable minimal residual disease
CR MRD negative rate at 9 months = treatment evaluation surveillance of cumulative toxicities of high dose rituximab

Secondary Outcome Measures

To determine and compare the progression free survival PFS
evaluate the immunophenotypic response rate after high dose Rituximab alone prephase in DenseR-FC
Treatment evaluation
To evaluate FcyRs polymorphisms influence on clinical response
R Dense arm treatment evaluation
To determine the pharmacokinetics of rituximab and determine the PK-PD relationship of rituximab based on biomarkers.
To evaluate the safety profile of higher doses of rituximab
5 months treatment and 36 months follow up
To determine the event-free survival EFS
To determine and compare the disease-free survival DFS
To determine the overall survival OS
To determine the time to next treatment TTNT

Full Information

First Posted
May 23, 2011
Last Updated
March 15, 2016
Sponsor
French Innovative Leukemia Organisation
Collaborators
Roche Pharma AG
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1. Study Identification

Unique Protocol Identification Number
NCT01370772
Brief Title
Intensified Rituimab Prephase Before FCR in Untreated B-CLL
Official Title
Phase II Multicentric, Randomized Trial, Exploring Intensified Rituximab Prephase Monotherapy Before Standard Fludarabine-Cyclophosphamide-Rituximab Regimen in Previously Untreated Symptomatic B-cell Chronic Lymphocytic Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2016
Overall Recruitment Status
Completed
Study Start Date
May 2011 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
French Innovative Leukemia Organisation
Collaborators
Roche Pharma AG

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Phase II, multicenter, randomized trial, exploring intensified Rituximab prephase monotherapy before standard Fludarabine-Cyclophosphamide-Rituximab FC-R regimen in previously untreated symptomatic B-cell chronic lymphocytic leukemia CLL. A Study from the Goelams GCFLLCMW intergroup
Detailed Description
Young fit medically B Cell untreated patients Comparison between FCR treatment = 6 FCR cycles and a the addition of a prephase with R Dense treatment before the 6 FCR cycles.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Chronic Lymphocytic Leukemia CLL
Keywords
B CLL, Fist line treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
140 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard R-FC arm
Arm Type
Active Comparator
Arm Description
Standard R-FC arm 6 cycles every 28 days Cycle 1: Rituximab : 375 mg/m² i.v on day 1 Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days For patients with Leucocyte count > 25* G/L : rituximab in two equal doses at D1, D2 Cycle 2-6: Rituximab: 500 mg/m² i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days
Arm Title
DenseR-FC arm
Arm Type
Experimental
Arm Description
DenseR-FC arm =1 prephase R Dense course +6 R-FC courses Prephase: - Rituximab: 500 mg on day 0, 2000 mg on days 1, 8, and D15 For patients with Leucocyte count > 25* G/L : rituximab 250 mg D-1, D0 prephase Cycle 1-6 (cycle 1 beginning at D22): Rituximab: 500 mg/m2 i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
R
Intervention Description
Cycle 1 Rituximab : 375 mg/m² i.v on day 1 Cycle 2-6 Rituximab:500 mg/m² i.v on day 1, repeated every 28 days
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
R
Intervention Description
Prephase: Rituximab:500 mg on day 0, 2000 mg on days 1, 8, and D15 Cycle 1-6 cycle 1 beginning at D22: Rituximab: 500 mg/m2 i.v on day 1, repeated every 28 days
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
C
Intervention Description
•FCR Cycle 1-6: Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
F
Intervention Description
FCR Cycle 1-6: Fludarabine :40 mg/m² per os, days 2-4, repeated every 28 days
Primary Outcome Measure Information:
Title
complete response rates according to IWCLL 2008 guidelines with undetectable minimal residual disease
Description
CR MRD negative rate at 9 months = treatment evaluation surveillance of cumulative toxicities of high dose rituximab
Time Frame
9 months
Secondary Outcome Measure Information:
Title
To determine and compare the progression free survival PFS
Time Frame
3 years
Title
evaluate the immunophenotypic response rate after high dose Rituximab alone prephase in DenseR-FC
Description
Treatment evaluation
Time Frame
9 months
Title
To evaluate FcyRs polymorphisms influence on clinical response
Description
R Dense arm treatment evaluation
Time Frame
9 months
Title
To determine the pharmacokinetics of rituximab and determine the PK-PD relationship of rituximab based on biomarkers.
Time Frame
12 months
Title
To evaluate the safety profile of higher doses of rituximab
Description
5 months treatment and 36 months follow up
Time Frame
41
Title
To determine the event-free survival EFS
Time Frame
3 years
Title
To determine and compare the disease-free survival DFS
Time Frame
3 years
Title
To determine the overall survival OS
Time Frame
3 years
Title
To determine the time to next treatment TTNT
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Patient information and written informed consent 18 years < Age < 66 ans confirmed B-CLL Matutes score 4 or 5 Binet stage C or Binet stage A and B with active disease could be considered for inclusion. For stage A with active disease an agreement of investigator coordinator is required. no prior treatment except steroids for less than 1 month (detail corticoid) No 17p deletion as assessed by FISH < 10 % positive nuclei Performance status ECOG < 2 CIRS Cumulative Illness Rating Scale < 6 Exclusion criteria: Binet stage A without active disease according to IWCLL 2008 criteria Know HIV seropositivity Hepatitis B or C seropositivity unless clearly due to vaccination Life expectancy < 6 months Clinically significant auto-immune anemia Active second malignancy currently requiring treatment (except basal cell carcinoma in situ endometrial carcinoma and incidental prostate carcinoma) and/or less than 5 years CR after breast cancer Any severe co-morbid conditions such as Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarythmias requiring ongoing treatment, severe chronic obstructive pulmonary disease with hypoxemia, uncontrolled diabetes mellitus, or uncontrolled hypertension Concomitant disease requiring prolonged use of corticosteroids > 1 month Known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs According to the SmPC or investigator practice Contraindication to use of Rituximab Transformation to aggressive B-cell malignancy e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukaemia Active bacterial, viral or fungal infection Abnormal renal function with creatinine clearance < 60 ml/min calculated according to the Cockcroft and Gault formula Total bilirubin, gamma glutamyltransferase or transaminase levels > 2.5 ULN. Any coexisting medical or psychological condition that would preclude participation in the required study procedures Patient with mental deficiency preventing proper understanding of the requirements of treatment. Pregnant or breastfeeding women. Adult under law-control Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study. No afiliate to social security
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guillaume CARTRON, MD PD
Organizational Affiliation
French Innovative Leukemia Organisation
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stephane LEPRETRE, MD
Organizational Affiliation
French Innovative Leukemia Organisation
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stephane LEPRETRE
City
Rouen
State/Province
CLCC Henri Becquerel
ZIP/Postal Code
76038
Country
France
Facility Name
Guillaume CARTRON
City
Montpellier
State/Province
Regional university Hospital
ZIP/Postal Code
34295
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36325355
Citation
Duroux-Richard I, Gagez AL, Alaterre E, Letestu R, Khalifa O, Jorgensen C, Lepretre S, Tchernonog E, Moreaux J, Cartron G, Apparailly F. miRNA profile at diagnosis predicts treatment outcome in patients with B-chronic lymphocytic leukemia: A FILO study. Front Immunol. 2022 Oct 17;13:983771. doi: 10.3389/fimmu.2022.983771. eCollection 2022.
Results Reference
derived
PubMed Identifier
28126961
Citation
Gagez AL, Duroux-Richard I, Lepretre S, Orsini-Piocelle F, Letestu R, De Guibert S, Tuaillon E, Leblond V, Khalifa O, Gouilleux-Gruart V, Banos A, Tournilhac O, Dupuis J, Jorgensen C, Cartron G, Apparailly F. miR-125b and miR-532-3p predict the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients. A French Innovative Leukemia Organization study. Haematologica. 2017 Apr;102(4):746-754. doi: 10.3324/haematol.2016.153189. Epub 2017 Jan 25.
Results Reference
derived
PubMed Identifier
27783363
Citation
Tout M, Gagez AL, Lepretre S, Gouilleux-Gruart V, Azzopardi N, Delmer A, Mercier M, Ysebaert L, Laribi K, Gonzalez H, Paintaud G, Cartron G, Ternant D. Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group. Clin Pharmacokinet. 2017 Jun;56(6):635-647. doi: 10.1007/s40262-016-0470-8.
Results Reference
derived
Links:
URL
http://www.filo-leucemie.org
Description
FILO Website

Learn more about this trial

Intensified Rituimab Prephase Before FCR in Untreated B-CLL

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