Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia (CLL-8)

This study has been completed.
Sponsor:
Collaborator:
German CLL Study Group
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00281918
First received: January 24, 2006
Last updated: September 9, 2013
Last verified: September 2013
Results First Received: December 21, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Leukemia
Interventions: Drug: Rituximab
Drug: Cyclophosphamide
Drug: Fludarabine Phosphate

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.
Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.

Participant Flow:   Overall Study
    Fludarabine+Cyclophosphamide (FC)     Fludarabine+Cyclophosphamide+Rituximab (FCR)  
STARTED     409 [1]   408 [2]
Safety Population; Received Study Drug     398     402  
COMPLETED     267 [3]   300 [3]
NOT COMPLETED     142     108  
[1] Informed consent unavailable for 2 patients at time of analysis; intent-to-treat population was 407.
[2] Informed consent unavailable for 5 patients at time of analysis; intent-to-treat population was 403.
[3] Completed all 6 cycles of study medication.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.
Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Total Total of all reporting groups

Baseline Measures
    Fludarabine+Cyclophosphamide (FC)     Fludarabine+Cyclophosphamide+Rituximab (FCR)     Total  
Number of Participants  
[units: participants]
  407     403     810  
Age  
[units: years]
Mean ± Standard Deviation
  59.3  ± 8.55     59.6  ± 8.70     59.5  ± 8.62  
Gender  
[units: participants]
     
Female     105     105     210  
Male     302     298     600  



  Outcome Measures
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1.  Primary:   Progression-free Survival (PFS)   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]

2.  Primary:   Final Analysis: Time to Progression-free Survival Event   [ Time Frame: Median observation time was approximately 66.4 months ]

3.  Secondary:   Event-free Survival (EFS)   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]
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Measure Type Secondary
Measure Title Event-free Survival (EFS)
Measure Description Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.
Time Frame Median observation time at time of analysis was approximately 21 months  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

Reporting Groups
  Description
Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.
Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.

Measured Values
    Fludarabine+Cyclophosphamide (FC)     Fludarabine+Cyclophosphamide+Rituximab (FCR)  
Number of Participants Analyzed  
[units: participants]
  407     403  
Event-free Survival (EFS)  
[units: Days]
Median ( Full Range )
  947.0  
  ( 1 to 1343 )  
  1212.0  
  ( 1 to 1372 )  


Statistical Analysis 1 for Event-free Survival (EFS)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
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[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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4.  Secondary:   Overall Survival (OS)   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]

5.  Secondary:   Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]

6.  Secondary:   Final Analysis: Time to Overall Survival Event   [ Time Frame: Median observation time was approximately 66.4 months ]

7.  Secondary:   Final Analysis: Time to Event-free Survival Event   [ Time Frame: Median observation time was approximately 66.4 months ]

8.  Secondary:   Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)   [ Time Frame: Median observation time was approximately 66.4 months ]

9.  Secondary:   Final Analysis: Duration of Response   [ Time Frame: Median observation time was approximately 66.4 months ]

10.  Secondary:   Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response   [ Time Frame: Median observation time was approximately 66.4 months ]

11.  Secondary:   Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)   [ Time Frame: Median observation time was approximately 66.4 months ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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