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
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

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
  Hide Baseline Characteristics

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.
No text entered.

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
  Hide All Outcome Measures

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

Measure Type Primary
Measure Title Progression-free Survival (PFS)
Measure Description Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
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 Intent-to-treat (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  
Progression-free Survival (PFS)  
[units: Days]
Median ( Full Range )
  981.0  
  ( 1 to 1343 )  
  1212.0  
  ( 1 to 1372 )  


Statistical Analysis 1 for Progression-free Survival (PFS)
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:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



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

Measure Type Primary
Measure Title Final Analysis: Time to Progression-free Survival Event
Measure Description Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, that included all randomized participants, with PFS events.

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]
  297     253  
Final Analysis: Time to Progression-free Survival Event  
[units: Days]
Median ( 95% Confidence Interval )
  998.0  
  ( 886 to 1129 )  
  1703.0  
  ( 1543 to 1853 )  


Statistical Analysis 1 for Final Analysis: Time to Progression-free Survival Event
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.57
95% Confidence Interval ( 0.48 to 0.67 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Event-free Survival (EFS)   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]

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:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



4.  Secondary:   Overall Survival (OS)   [ Time Frame: Median observation time at time of analysis was approximately 21 months ]

Measure Type Secondary
Measure Title Overall Survival (OS)
Measure Description Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.
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  
Overall Survival (OS)  
[units: Days]
   
Minimum number of days to an event     5     4  
Maximum number of days to an event     1373     1372  


Statistical Analysis 1 for Overall Survival (OS)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0427
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



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 ]

Measure Type Secondary
Measure Title Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).
Measure Description CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.
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  
Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).  
[units: Days to an event]
   
Minimum number of days to an event     84     91  
Maximum number of days to an event     1164     1226  


Statistical Analysis 1 for Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.7882
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



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

Measure Type Secondary
Measure Title Final Analysis: Time to Overall Survival Event
Measure Description Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, that included all randomized participants who died.

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]
  154     125  
Final Analysis: Time to Overall Survival Event  
[units: Days]
Median ( 95% Confidence Interval )
  2613.0  
  ( 2354 to NA ) [1]
  NA  
  ( 2745 to NA ) [2]
[1] Upper limit of the 95% confidence interval has not been reached.
[2] Median time to event and upper limit of the 95% confidence have not been reached.


Statistical Analysis 1 for Final Analysis: Time to Overall Survival Event
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0010
Hazard Ratio (HR) [4] 0.68
95% Confidence Interval ( 0.54 to 0.86 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title Final Analysis: Time to Event-free Survival Event
Measure Description Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, that included all randomized participants, with disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death.

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]
  301     257  
Final Analysis: Time to Event-free Survival Event  
[units: Days]
Median ( 95% Confidence Interval )
  951.0  
  ( 843 to 1039 )  
  1666.0  
  ( 1415 to 1799 )  


Statistical Analysis 1 for Final Analysis: Time to Event-free Survival Event
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.57
95% Confidence Interval ( 0.48 to 0.67 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)
Measure Description CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, all randomized participants, with complete response who experienced a disease free survival event (disease relapse or death).

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]
  58     97  
Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)  
[units: Days]
Median ( 95% Confidence Interval )
  1488.0  
  ( 1198 to 1836 )  
  1854.0  
  ( 1646 to 2208 )  


Statistical Analysis 1 for Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0523
Hazard Ratio (HR) [4] 0.73
95% Confidence Interval ( 0.52 to 1.02 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title Final Analysis: Duration of Response
Measure Description Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, all randomized participants, with complete response or partial response who experienced an event (disease progression or death due to any cause).

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]
  214     207  
Final Analysis: Duration of Response  
[units: Days]
Median ( 95% Confidence Interval )
  1102.0  
  ( 977 to 1249 )  
  1718.0  
  ( 1618 to 1859 )  


Statistical Analysis 1 for Final Analysis: Duration of Response
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.58
95% Confidence Interval ( 0.48 to 0.71 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response
Measure Description CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.
Time Frame Median observation time was approximately 66.4 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.
Intent-to-treat population included all randomized participants.

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]
  409     408  
Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
  72.4  
  ( 67.8 to 76.7 )  
  85.8  
  ( 82.0 to 89.0 )  


Statistical Analysis 1 for Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response
Groups [1] All groups
Method [2] Chi-squared
P Value [3] <.0001
Odds Ratio (OR) [4] 2.30
95% Confidence Interval ( 1.62 to 3.28 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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11.  Secondary:   Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)   [ Time Frame: Median observation time was approximately 66.4 months ]

Measure Type Secondary
Measure Title Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)
Measure Description The time from randomization to the start of a new treatment.
Time Frame Median observation time was approximately 66.4 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.
Participants from the Intent-to-treat population, that included all randomized participants, who started a new CLL treatment.

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]
  251     206  
Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)  
[units: Days]
Median ( 95% Confidence Interval )
  1455.0  
  ( 1324 to 1577 )  
  2082.0  
  ( 1926 to 2253 )  


Statistical Analysis 1 for Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.59
95% Confidence Interval ( 0.49 to 0.72 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[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] Other relevant estimation information:
  No text entered.




  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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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann-LaRoche
phone: 800-821-8590


No publications provided by Hoffmann-La Roche

Publications automatically indexed to this study:


Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00281918     History of Changes
Other Study ID Numbers: CDR0000454560, GCLLSG-CLL-8, EU-20560, ML17102
Study First Received: January 24, 2006
Results First Received: December 21, 2009
Last Updated: September 9, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices