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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 
Overall Participants Analyzed 
[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 
[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.
World Health Organization (WHO) Performance Status [1] 
[Units: Participants]
     
WHO Performance Status = 0   81   72   153 
WHO Performance Status = 1   87   95   182 
[1] 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."
Rai Stage Group [1] 
[Units: Participants]
     
Rai Stage 0   2   2   4 
Rai Stage I - II   104   102   206 
Rai Stage III - IV   62   63   125 
[1]

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.

Binet Stage [1] 
[Units: Participants]
     
Binet Stage A   27   25   52 
Binet Stage B   89   89   178 
Binet Stage C   52   53   105 
[1]

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).

Disease Status [1] 
[Units: Participants]
     
Relapsed   101   101   202 
Refractory   67   66   133 
[1] Count of participants with refractory or relapsed disease at baseline (as reported by the investigator).
Summary of Prior Therapy by Type of Therapy [1] 
[Units: Participants]
     
Fludarabine-containing therapy   25   26   51 
Non-fludarabine-containing therapy   143   141   284 
[1] 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 ]

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


  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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  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.


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


Publications of Results:
Engert A, et al. Overall Survival Advantage and Acceptable Safety Profile with Fludarabine in Combination with Alemtuzumab (FluCam) in Previously Treated Patients with Advanced Stage Chronic Lymphocytic Leukemia. Poster Presentation at American Society of Hematology 10 December 2010; Blood (ASH Annual Meeting Abstracts), Nov 2010;116:919. http://ash.confex.com/ash/2010/webprogram/Paper31687.html
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
Engert A, et al. Fludarabine (FLU) plus Alemtuzumab (FluCAM) Improves Progression Free Survival versus Fludarabine in Previously Treated Chronic Lymphocytic Leukemia and Demonstrates Activity in High Risk Patients. Poster Presentation at European Hematology Association 12 June 2010. Abstract 0768. http://www.eventure-online.com/eventure/publicAbstractView.do?id=136964&congressId=3446

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00086580     History of Changes
Other Study ID Numbers: CAM314
2004-000149-39 ( EudraCT Number )
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