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Fludarabine, Cyclophosphamide, and Rituximab or Alemtuzumab in Treating CLL2007 CLL 2007 FMP

Primary Purpose

Leukemia

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Campath
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 Leukemia focused on measuring B-cell chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia

Eligibility Criteria

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

DISEASE CHARACTERISTICS:

Inclusion

Diagnosis of B-cell chronic lymphocytic leukemia (CLL), meeting the following criteria:

  • Binet classification stages B or C
  • Del 17 p (FISH) negative (< 10 % positives cores)
  • Matutes score 4 or 5

Exclusion Transformation to aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

Exclusion ECOG performance status ≥ 2

  • Life expectancy < 6 months
  • Creatinine clearance < 60 mL/min
  • Total bilirubin > 2 x upper limit of normal (ULN)
  • Gamma glutamyltransferase or transaminase levels > 2 x ULN
  • Cumulative illness rating scale > 6
  • HIV seropositivity
  • Hepatitis B or C seropositivity (unless clearly due to vaccination)
  • Clinically significant autoimmune anemia
  • Active bacterial, viral, or fungal infection
  • Active second malignancy currently requiring treatment (except basal cell carcinoma or in situ endometrial carcinoma) and/or less than 5 years complete remission after breast cancer

  • Any severe comorbid conditions including, but not limited to, any of the following:

    • Class III or IV heart failure
    • Recent myocardial infarction
    • Unstable angina
    • Ventricular tachyarrhythmias requiring ongoing treatment
    • Severe chronic obstructive pulmonary disease with hypoxemia
    • Uncontrolled diabetes mellitus
    • 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
  • Contraindication to the use of rituximab or alemtuzumab according to Summary of Product Characteristics
  • Any coexisting medical or psychological condition that would preclude participation in the required study procedures
  • Any mental deficiency preventing proper understanding of the requirements of treatment
  • Person under law control
  • Pregnant or breastfeeding women
  • Fertile 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

PRIOR CONCURRENT THERAPY:

Inclusion

  • No prior chemotherapy, radiotherapy, or immunotherapy for CLL
  • Corticosteroids within the past month allowed

Sites / Locations

  • Centre Henri Becquerel

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

FCCAM

FCR

Arm Description

Fludarabine-Cyclophosphamide-Campath (FCCam) Oral Fludarabine: 40 mg/m2 per os, D1 to D3 Oral Cyclophosphamide: 250 mg/m2/day as one dose at noon, D1 to D3 Campath®: 30 mg sc, D1 to D3 without dose escalation

Fludarabine-Cyclophosphamide-Rituximab (FCR) First course: Rituximab 375 mg/m2 on D1. D2 to D4: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon Subsequent courses (2 to 6) Rituximab 500 mg/m2 on D1 D1 to D3: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon

Outcomes

Primary Outcome Measures

Progression-free survival at 36 months

Secondary Outcome Measures

Disease-free survival
Event-free survival
Overall survival
Time to next treatment
Overall response rate (complete response [CR] and partial response [PR])
Duration of phenotypic, molecular, NCI complete and partial responses
Response rates and survival times in biological subgroups
Treatment-related adverse effects

Full Information

First Posted
November 27, 2007
Last Updated
July 24, 2013
Sponsor
French Innovative Leukemia Organisation
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1. Study Identification

Unique Protocol Identification Number
NCT00564512
Brief Title
Fludarabine, Cyclophosphamide, and Rituximab or Alemtuzumab in Treating CLL2007 CLL 2007 FMP
Official Title
Randomized Phase-III Trial Comparing Fludarabine and Cyclophosphamide Plus Rituximab (FCR) to FC and MabCampath (FCCam) for Previously Untreated Fit Patients With Chronic Lymphocytic Leukemia (CLL)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2009
Overall Recruitment Status
Completed
Study Start Date
November 2007 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
French Innovative Leukemia Organisation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to kill cancer cells or stop them from growing. Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. It is not yet known whether giving fludarabine and cyclophosphamide together with rituximab is more effective than giving fludarabine and cyclophosphamide together with alemtuzumab in treating B-cell chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying giving fludarabine together with cyclophosphamide and rituximab to see how well it works as first-line therapy compared with giving fludarabine together with cyclophosphamide and alemtuzumab in treating patients with B-cell chronic lymphocytic leukemia.
Detailed Description
OBJECTIVES: Primary To compare 36-month progression-free survival in patients with Binet stage B or C B-cell chronic lymphocytic leukemia treated with first-line therapy comprising fludarabine phosphate and cyclophosphamide and either rituximab or alemtuzumab. Secondary To compare the disease-free survival, event-free survival, and overall survival of patients treated with these regimens. To compare time to next treatment in patients treated with these regimens. To compare the overall response rate (complete response [CR] and partial response [PR]) in patients treated with these regimens. To compare the rate of phenotypic and molecular response in patients treated with these regimens. To compare the duration of phenotypic, molecular, complete and partial responses in patients treated with these regimens. To compare the response rates and survival times in biological subgroups. To compare the rates of treatment-related adverse effects in patients treated with these regimens. To compare the quality of life of patients treated with these regimens. Minimal residual disease study. OUTLINE: This is a multicenter study. Patients are stratified according to Ig mutational status and cytogenetic abnormalities. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive rituximab IV on day 1 and fludarabine phosphate and cyclophosphamide IV or orally on days 2-4 of course 1. Beginning in course 2 and for all subsequent courses, patients receive rituximab IV on day 1 and fludarabine phosphate and cyclophosphamide IV or orally on days 1-3. Arm II: Patients receive alemtuzumab subcutaneously, oral fludarabine phosphate, and oral cyclophosphamide on days 1-3. In both arms, treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
B-cell chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
178 (Actual)

8. Arms, Groups, and Interventions

Arm Title
FCCAM
Arm Type
Experimental
Arm Description
Fludarabine-Cyclophosphamide-Campath (FCCam) Oral Fludarabine: 40 mg/m2 per os, D1 to D3 Oral Cyclophosphamide: 250 mg/m2/day as one dose at noon, D1 to D3 Campath®: 30 mg sc, D1 to D3 without dose escalation
Arm Title
FCR
Arm Type
Active Comparator
Arm Description
Fludarabine-Cyclophosphamide-Rituximab (FCR) First course: Rituximab 375 mg/m2 on D1. D2 to D4: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon Subsequent courses (2 to 6) Rituximab 500 mg/m2 on D1 D1 to D3: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon
Intervention Type
Biological
Intervention Name(s)
Campath
Other Intervention Name(s)
Alemtuzumab
Intervention Description
Fludarabine-Cyclophosphamide-Campath (FCCam)
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
Mabthera®
Intervention Description
Fludarabine-Cyclophosphamide-Rituximab (FCR)
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Endoxan®
Intervention Description
Fludarabine-Cyclophosphamide-Campath (FCCAM) Fludarabine-Cyclophosphamide-Rituximab (FCR)
Intervention Type
Drug
Intervention Name(s)
fludarabine
Other Intervention Name(s)
Fludara®
Intervention Description
Fludarabine-Cyclophosphamide-Campath (FCCAM) Fludarabine-Cyclophosphamide-Rituximab (FCR)
Primary Outcome Measure Information:
Title
Progression-free survival at 36 months
Time Frame
36 months follow up
Secondary Outcome Measure Information:
Title
Disease-free survival
Time Frame
36 months follow up
Title
Event-free survival
Time Frame
36 months follow up
Title
Overall survival
Time Frame
36 months follow up
Title
Time to next treatment
Time Frame
36 months follow up
Title
Overall response rate (complete response [CR] and partial response [PR])
Time Frame
36 months follow up
Title
Duration of phenotypic, molecular, NCI complete and partial responses
Time Frame
36 months follow up
Title
Response rates and survival times in biological subgroups
Time Frame
36 months follow up
Title
Treatment-related adverse effects
Time Frame
36 months follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Inclusion Diagnosis of B-cell chronic lymphocytic leukemia (CLL), meeting the following criteria: Binet classification stages B or C Del 17 p (FISH) negative (< 10 % positives cores) Matutes score 4 or 5 Exclusion Transformation to aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia) PATIENT CHARACTERISTICS: Exclusion ECOG performance status ≥ 2 Life expectancy < 6 months Creatinine clearance < 60 mL/min Total bilirubin > 2 x upper limit of normal (ULN) Gamma glutamyltransferase or transaminase levels > 2 x ULN Cumulative illness rating scale > 6 HIV seropositivity Hepatitis B or C seropositivity (unless clearly due to vaccination) Clinically significant autoimmune anemia Active bacterial, viral, or fungal infection Active second malignancy currently requiring treatment (except basal cell carcinoma or in situ endometrial carcinoma) and/or less than 5 years complete remission after breast cancer Any severe comorbid conditions including, but not limited to, any of the following: Class III or IV heart failure Recent myocardial infarction Unstable angina Ventricular tachyarrhythmias requiring ongoing treatment Severe chronic obstructive pulmonary disease with hypoxemia Uncontrolled diabetes mellitus 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 Contraindication to the use of rituximab or alemtuzumab according to Summary of Product Characteristics Any coexisting medical or psychological condition that would preclude participation in the required study procedures Any mental deficiency preventing proper understanding of the requirements of treatment Person under law control Pregnant or breastfeeding women Fertile 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 PRIOR CONCURRENT THERAPY: Inclusion No prior chemotherapy, radiotherapy, or immunotherapy for CLL Corticosteroids within the past month allowed
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephane Lepretre, MD
Organizational Affiliation
Centre Henri Becquerel
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Pierre Feugier
Organizational Affiliation
CHU de Nancy - Hopitaux de Brabois
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Roselyne DELEPINE, mrs
Organizational Affiliation
Groupe Est Ouest Etudes leucemies et Autres Maladies du Sang
Official's Role
Study Director
Facility Information:
Facility Name
Centre Henri Becquerel
City
Rouen
ZIP/Postal Code
76038
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
29567785
Citation
Grgurevic S, Montilla-Perez P, Bradbury A, Gilhodes J, Queille S, Pelofy S, Bancaud A, Filleron T, Ysebaert L, Recher C, Laurent G, Fournie JJ, Cazaux C, Quillet-Mary A, Hoffmann JS. DNA polymerase nu gene expression influences fludarabine resistance in chronic lymphocytic leukemia independently of p53 status. Haematologica. 2018 Jun;103(6):1038-1046. doi: 10.3324/haematol.2017.174243. Epub 2018 Mar 22.
Results Reference
derived
PubMed Identifier
22337714
Citation
Lepretre S, Aurran T, Mahe B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delepine R, Vaudaux S, Van Den Neste E, Bene MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. doi: 10.1182/blood-2011-07-365437. Epub 2012 Feb 14.
Results Reference
derived

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Fludarabine, Cyclophosphamide, and Rituximab or Alemtuzumab in Treating CLL2007 CLL 2007 FMP

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