Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00086580
First received: July 6, 2004
Last updated: February 10, 2014
Last verified: February 2014
Results First Received: June 13, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: B-Cell Chronic Lymphocytic Leukemia
Interventions: Biological: FluCAM [Fludara + Campath]
Biological: 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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Treatment was from initiation of study drug(s) to 4 weeks after last administration of study drug. Follow-up was for those without disease progression and ended upon disease progression or primary endpoint analysis whichever came first. Observation included those with disease progression who were observed for alternative rx and overall survival.

Reporting Groups
  Description
Combination Arm (FluCAM) Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.
Fludarabine Alone Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.

Participant Flow for 3 periods

Period 1:   Treatment Period
    Combination Arm (FluCAM)     Fludarabine Alone  
STARTED     168     167  
Safety Population     164 [1]   165 [2]
COMPLETED     103 [3]   107 [4]
NOT COMPLETED     65     60  
Disease progression                 9                 8  
Unable to comply with protocol                 3                 1  
Withdrawal by Subject                 7                 8  
Physician Decision                 13                 7  
AE - not treatment related                 7                 7  
Toxicity - treatment related                 15                 15  
Anemia or thrombocytopenia                 1                 4  
Death                 5                 7  
Not specified                 5                 3  
[1] Four participants did not receive treatment
[2] Two participants did not receive treatment
[3] Finished 6 cycles of study drugs
[4] Finished 6 cycles of study drug

Period 2:   Follow-up Period
    Combination Arm (FluCAM)     Fludarabine Alone  
STARTED     141     137  
COMPLETED     37     18  
NOT COMPLETED     104     119  
Disease progression                 72                 99  
Unable to comply with protocol                 5                 0  
Withdrawal by Subject                 6                 6  
Physician Decision                 0                 1  
AE - not related                 1                 0  
Death                 13                 7  
Not specified                 7                 6  

Period 3:   Observation Period
    Combination Arm (FluCAM)     Fludarabine Alone  
STARTED     95     121  
COMPLETED     49     56  
NOT COMPLETED     46     65  
Unable to comply with protocol                 1                 1  
Withdrawal by Subject                 4                 2  
Death                 33                 55  
Not specified                 8                 7  



  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.
No text entered.

Reporting Groups
  Description
Combination Arm (FluCAM) Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.
Fludarabine Alone Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.
Total Total of all reporting groups

Baseline Measures
    Combination Arm (FluCAM)     Fludarabine Alone     Total  
Number of Participants  
[units: participants]
  168     167     335  
Age  
[units: years]
Mean ± Standard Deviation
  60.0  ± 9.25     60.8  ± 9.34     60.4  ± 9.29  
Gender  
[units: participants]
     
Female     59     59     118  
Male     109     108     217  
Race/Ethnicity, Customized  
[units: participants]
     
White     167     167     334  
Other     1     0     1  
Height  
[units: centimeters]
Mean ± Standard Deviation
  169.0  ± 8.88     169.4  ± 9.30     169.2  ± 9.08  
Body Surface Area (BSA)  
[units: meters^2]
Mean ± Standard Deviation
  1.87  ± 0.213     1.90  ± 0.218     1.88  ± 0.216  
Maximum Lymph Node Size [1]
[units: participants]
     
<5 centimeters     134     136     270  
>= 5 centimeters     34     31     65  
World Health Organization (WHO) Performance Status [2]
[units: participants]
     
WHO Performance Status = 0     81     72     153  
WHO Performance Status = 1     87     95     182  
Rai Stage Group [3]
[units: participants]
     
Rai Stage 0     2     2     4  
Rai Stage I - II     104     102     206  
Rai Stage III - IV     62     63     125  
Binet Stage [4]
[units: participants]
     
Binet Stage A     27     25     52  
Binet Stage B     89     89     178  
Binet Stage C     52     53     105  
Disease Status [5]
[units: participants]
     
Relapsed     101     101     202  
Refractory     67     66     133  
Summary of Prior Therapy by Type of Therapy [6]
[units: participants]
     
Fludarabine-containing therapy     25     26     51  
Non-fludarabine-containing therapy     143     141     284  
[1] The number of participants whose largest lymph node by physical exam assessment during a baseline visit fell within two categories: <5 cm and >=5 cm. If there is no enlarged lymph node, then size is classified as <5 cm.
[2] Per protocol, all participants had a WHO performance status of 0 or 1. A WHO performance status of 0 is defined as "patient is able to carry out all normal activity without restriction," and status of 1 is "patient is ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours."
[3]

Rai staging is a way to categorize the disease progression of chronic lymphocytic leukemia (CLL); higher stages reflect increasing severity.

Rai Stage 0: Lymphocytosis only, Rai Stage I: Lymphocytosis with lymphadenopathy, Rai Stage II: Lymphocytosis with hepatomegaly or splenomegaly, Rai Stage III: Lymphocytosis with anemia, Rai Stage IV: Lymphocytosis with thrombocytopenia.

Per protocol, the 4 participants with Rai Stage 0 were eligible for the study because they had Binet Stage A.

[4]

Binet staging classifies CLL according to the number of lymphoid tissues involved, as well as the presence of low red blood cell count (anemia) or low number of blood platelets (thrombocytopenia).

Binet Stage A: fewer than three areas of enlarged lymphoid tissue. Enlarged lymph nodes of the neck, underarms, and groin, as well as the spleen, are each considered "one group," whether unilateral (one-sided) or bilateral (on both sides).

Binet Stage B: more than three areas of enlarged lymphoid tissue.

Binet Stage C: anemia plus thrombocytopenia (platelets <100 x 10^3/dL).

[5] Count of participants with refractory or relapsed disease at baseline (as reported by the investigator).
[6] Count of participants who had prior therapy categorized by type of therapy: fludarabine-containing therapy or non-fludarabine-containing therapy.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment   [ Time Frame: Up to 6 years ]

2.  Secondary:   Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)   [ Time Frame: Up to 9 months ]

3.  Secondary:   Kaplan-Meier Estimates of Overall Survival Time   [ Time Frame: Up to 6 years ]

4.  Secondary:   Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)   [ Time Frame: Up to 6 years ]

5.  Secondary:   Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)   [ Time Frame: Up to 6 years ]

6.  Secondary:   Kaplan-Meier Estimates for Time to Alternative Therapy   [ Time Frame: Up to 6 years ]

7.  Secondary:   Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline   [ Time Frame: Day 0 (baseline) ]

8.  Secondary:   Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment   [ Time Frame: up to month 6 (end of treatment) ]

9.  Secondary:   Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline   [ Time Frame: Day 0 (baseline) ]

10.  Secondary:   Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment   [ Time Frame: up to month 6 (end of treatment) ]

11.  Secondary:   Summary of Participants With Adverse Experiences (AEs)   [ Time Frame: Up to 6 years ]
  Hide Outcome Measure 11

Measure Type Secondary
Measure Title Summary of Participants With Adverse Experiences (AEs)
Measure Description Number of participants with adverse events (AEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (4 point scale from 'not related' to 'definitely related'). Categories reported include participant counts for treatment-emergent AEs, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), and deaths. Related AEs for the combination arm can be related to either fludarabine or alemtuzumab.
Time Frame Up to 6 years  
Safety Issue Yes  

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.
Safety population

Reporting Groups
  Description
Combination Arm (FluCAM) Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle.
Fludarabine Alone Participants received fludarabine monotherapy 25 mg/m^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles.

Measured Values
    Combination Arm (FluCAM)     Fludarabine Alone  
Number of Participants Analyzed  
[units: participants]
  164     165  
Summary of Participants With Adverse Experiences (AEs)  
[units: participants]
   
At least 1 treatment emergent AE     161     149  
At least 1 related treatment emergent AE     159     125  
At least 1 treatment-emergent infection     67     58  
At least 1 drug-related infection     44     30  
At least 1 serious AE     54     41  
At least 1 related serious AE     47     28  
Discontinuation of study drug due to AE     37     32  
Discontinuation of study drug due to related AE     32     24  
Deaths     10     12  
Patients who died due to a related AE     7     6  
Patients who died within 30 days of the last dose     4     7  

No statistical analysis provided for Summary of Participants With Adverse Experiences (AEs)



12.  Secondary:   Mean Systemic Clearance (CL) of Fludarabine   [ Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) ]

13.  Secondary:   Total Volume of Distribution (Vss) of Fludarabine   [ Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) ]

14.  Secondary:   Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)   [ Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) ]

15.  Secondary:   Maximum Plasma Concentration (Cmax) of Fludarabine   [ Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) ]

16.  Secondary:   Participants With Minimal Residual Disease (MRD)   [ Time Frame: up to 9 months ]

17.  Other Pre-specified:   Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II   [ Time Frame: Up to 6 years ]

18.  Other Pre-specified:   Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV   [ Time Frame: Up to 6 years ]

19.  Other Pre-specified:   Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II   [ Time Frame: Up to 6 years ]

20.  Other Pre-specified:   Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV   [ Time Frame: Up to 6 years ]


  Serious Adverse Events


  Other Adverse Events


  More Information
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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.


Limitations and Caveats
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
No text entered.  


Results Point of Contact:  
Name/Title: Genzyme Medical Information
Organization: Genzyme Corporation
phone: 800-745-4447


Publications of Results:
Engert A, et al. Improved Progression-free Survival (PFS) of Alemtuzumab (Campath®, MabCampath®) plus Fludarabine (Fludara®) versus Fludarabine Alone as Second-line Treatment of Patients with B-Cell Chronic Lymphocytic Leukemia: Preliminary Results from a Phase III Randomized Trial. 51st ASH Annual Meeting. Blood 2009;114. Abstract 537. http://ash.confex.com/ash/2009/webprogram/Paper21929.html

Publications automatically indexed to this study:

Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00086580     History of Changes
Other Study ID Numbers: CAM314, 2004-000149-39
Study First Received: July 6, 2004
Results First Received: June 13, 2011
Last Updated: February 10, 2014
Health Authority: United States: Food and Drug Administration
Austria: Federal Ministry for Health and Women
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
Croatia: Ministry of Health and Social Care
Czech Republic: State Institute for Drug Control
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Italy: Ministry of Health
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Ministry of Health of the Russian Federation
Sweden: Medical Products Agency
Ukraine: State Pharmacological Center - Ministry of Health