Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients
- Conditions
- B-Cell Chronic Lymphocytic Leukemia
- Interventions
- Biological: fludarabine phosphateBiological: FluCAM [Fludara + Campath]
- Registration Number
- NCT00086580
- Lead Sponsor
- Genzyme, a Sanofi Company
- Brief Summary
This is a Phase 3, prospective, multicenter, open-label, randomized, controlled study to evaluate and compare the efficacy and safety of fludarabine plus alemtuzumab versus fludarabine alone as second-line therapy for patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). Patients who meet all eligibility criteria and sign the informed consent document may be entered on the study.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 335
- A diagnosis of B-cell chronic lymphocytic leukemia (B-CLL); according to the National Cancer Institute Working Group (NCI WG) criteria.
- Relapsed or refractory disease after 1 prior regimen except patients who were refractory to (i.e., progressed on) fludarabine or alemtuzumab therapy. Patients who previously responded (complete response or partial response) to fludarabine or alemtuzumab therapy, but who have relapsed at the time of study entry, may be eligible but response to fludarabine or alemtuzumab therapy must have lasted >12 months (i.e., >12 months from a documented response to a documented relapse).
- Binet stage A, stage B, or stage C or Rai Stage I through IV disease with evidence of progression as evidenced by the presence of one or more of the following:
I. Evidence of progressive marrow failure as manifested by: 1) a decrease in hemoglobin to <11g/dL, or 2) a decrease in platelet count to <100 x 10^9/L within the previous 6 months, or 3) a decrease in absolute neutrophil count (ANC) to <1.0 X 10^9/L.
II. Progressive splenomegaly to >2 cm below the left costal margin or other organomegaly.
III. Progressive lymphadenopathy.
IV. Progressive lymphocytosis with an increase of 50% over a 2-month period, or an anticipated doubling time of less than 6 months.
- World Health Organization (WHO) performance status (PS) of 0 or 1.
- Life expectancy >12 weeks.
- Anti-cancer therapy, major surgery, or irradiation was completed >3 weeks before randomization in this study. Patient must have recovered from the acute side effects incurred as a result of previous therapy.
- Serum creatinine less than or equal to 2.0 x institutional upper limits of normal (ULN) and calculated creatinine clearance (CrCl) greater than or equal to 30mL/min using the Cockroft and Gault formula.
- Adequate liver function as indicated by a total bilirubin, AST, and ALT less than or equal to 2 x the institutional ULN value, unless directly attributable to the patient's tumor.
- Female patients with childbearing potential must have a negative serum pregnancy test with 2 weeks of first dose of study drug(s). Male and female patients must agree to use an effective contraceptive method while on study treatment, if appropriate, and for a minimum of 6 months following study therapy.
- Signed, written informed consent.
- Previously treated with >1 prior regimen for B-CLL.
- Previously treated with a fludarabine plus alemtuzumab (FluCAM) regimen for B-CLL.
- Positive Coombs test and actively hemolyzing.
- Absolute neutrophil count (ANC) <1.5 x 10^9/L or platelet count <75 x 10^9/L, unless due to bone marrow involvement.
- Medical condition requiring chronic use of pharmacologic doses of oral corticosteroids, i.e. anything other than replacement dose levels.
- History of anaphylaxis following exposure to monoclonal antibodies.
- Use of investigational agents within 6 weeks prior to study randomization.
- Active infection or history of severe infection (grade 4) within 3 months prior to study randomization.
- Known to be human immunodeficiency virus (HIV) positive.
- Autoimmune thrombocytopenia.
- Active second malignancy.
- Known central nervous system (CNS) involvement with B-CLL.
- Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (Class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (chronic obstructive pulmonary disease [COPD] with hypoxemia), or major organ malfunction (liver, kidney) that could interfere with the patient's ability to participate in the study.
- Pregnant or nursing women.
- Patients that have progressed with more aggressive B-cell cancers such as Richter's syndrome.
- Active hepatitis or a history of prior viral hepatitis B or hepatitis C, or positive hepatitis B serologies without prior immunization.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Fludarabine Alone fludarabine phosphate - Combination Arm (FluCAM) FluCAM [Fludara + Campath] -
- Primary Outcome Measures
Name Time Method Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment Up to 6 years Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months.
- Secondary Outcome Measures
Name Time Method Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) Up to 9 months Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology.
Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment up to month 6 (end of treatment) EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Kaplan-Meier Estimates of Overall Survival Time Up to 6 years Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months.
Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) Up to 6 years Time to disease progression was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease as determined by IRRP. Results are stated in months.
Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) Up to 6 years Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease as determined by IRRP or death due to any cause. Results are stated in months.
Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline Day 0 (baseline) The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Kaplan-Meier Estimates for Time to Alternative Therapy Up to 6 years Time to alternative therapy was defined as the number of days from the date of randomization to the date of first alternative therapy for chronic lymphocytic leukemia (CLL) or death resulting from any cause. Participants who had not received alternative therapy as of the data cutoff date were censored at the last follow-up visit assessment date plus 1 day. Results are stated in months.
Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline Day 0 (baseline) EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment up to month 6 (end of treatment) The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual "thermometer" with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Summary of Participants With Adverse Experiences (AEs) Up to 6 years 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.
Mean Systemic Clearance (CL) of Fludarabine 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) Clearance of drug from plasma is affected by the absorption, distribution, metabolism and elimination of the drug. Mean systemic clearance of fludarabine is derived from plasma concentration versus time data.
Total Volume of Distribution (Vss) of Fludarabine 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) The total volume of distribution (Vss) is the apparent volume in which fludarabine is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues. Total volume of distribution (Vss) of fludarabine is derived from plasma concentration versus time data.
Participants With Minimal Residual Disease (MRD) up to 9 months MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. MRD was assessed in participants with a clinical complete response (CR) or partial response (PR) without recovery of blood counts. MRD represents a very positive outcome.
Maximum Plasma Concentration (Cmax) of Fludarabine 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) Cmax is the maximum plasma concentration of fludarabine observed.
Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau) 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) AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau).
Trial Locations
- Locations (48)
University Hospital Dubrava
🇭🇷Zagreb, Croatia
Clinical Hospital Merkur
🇭🇷Zagreb, Croatia
Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku
🇵🇱Wroclaw, Poland
Saint-Petersburg GUZ "City Hospital #31" 3, Dynamo Prospect
🇷🇺Saint-Petersburg, Russian Federation
GU "Main Military Clinical Hospital named after acad. N.N.Burdenko of MO of Russia", Haematology Centre 3
🇷🇺Moscow, Russian Federation
Institutol Clinic Fundeni, Clinica Heamtologie
🇷🇴Bucharest, Romania
Cherkasskly Oncology Dispensary
🇺🇦Cherkasy, Ukraine
City Clinical Hospital #4, Regional Hematology Center
🇺🇦Dnepropetrovsk, Ukraine
Florida Cancer Specialists
🇺🇸Fort Myers, Florida, United States
Multiprofile Hospital for Active Treatment, St. Marina
🇧🇬Varna, Bulgaria
UMHAT St. Georgi, Hematology Clinic
🇧🇬Plovdiv, Bulgaria
Clinical Hospital Center Rijeka, Department of Haematology
🇭🇷Rijeka, Croatia
Universitat Wien AKH, Innere Medizin I
🇦🇹Wien, Austria
Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin
🇩🇪Koln, Germany
Medizinische Universitatsklinik Graz
🇦🇹Graz, Austria
University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski
🇧🇬Pleven, Bulgaria
Hopital Notre-Dame du CHUM
🇨🇦Montreal, Quebec, Canada
Cancer Care Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin
🇩🇪Berlin, Germany
Klinika Hematologii AM
🇵🇱Lodz, Poland
Hospital de Santa Maria Servico de Hematologia Clinica/Hospital de dia de Hematologia
🇵🇹Lisboa, Portugal
Hospital de Sao Teotonio, Servico de Hematologia/Hosptial de Dia Oncologico
🇵🇹Viseu, Portugal
Khmelnitskiy Regional Hospital, Hematology Department
🇺🇦Khmelnitskiy, Ukraine
Institute of Hematology and Transfusiology AMS of Ukraine, City Clinical Hospital #9
🇺🇦Kiev, Ukraine
U.O. Oncologia Medica Azienda Ospedaliera "Pugliese-Ciaccio"
🇮🇹Cantanzaro, Italy
Robert-Bosch Krankenhaus GmbH
🇩🇪Stuttgart, Germany
CHRU - Hopital Claude Huriez
🇫🇷Lille, Cedex, France
Charite Universitatsklinikum der Humboldt-Universitat zu Berlin
🇩🇪Berlin, Germany
Unita Operativa di Medicina Generale Reumatologia e Oncoematologia
🇮🇹Milano, Italy
Istituto di Ematologia Dipartmento di Biotechnologie Celluari ed Ematologia, Universita di Roma "La Sapienza"
🇮🇹Rome, Italy
University Hospital, Dept. of Hematology
🇸🇪Lund, Sweden
Universitetssjukhuset
🇸🇪Orebro, Sweden
Orebro University Hospital, Dep. of Medicine
🇸🇪Orebro, Sweden
Medicin kliniken/Hematologsektionen
🇸🇪Sundsvall, Sweden
Akademiska sjukhuset
🇸🇪Uppsala, Sweden
Kharkov Regional Clinical Oncology Center, Department of Hematology
🇺🇦Kharkov, Ukraine
Institute of Oncology AMS of Ukraine
🇺🇦Kiev, Ukraine
Scientific Centre for Radiation Medicine AMS of Ukraine, Dept of Hematology and Transplantology
🇺🇦Kyiv, Ukraine
Lviv National Medical University named Danilo Galytcky
🇺🇦Lviv, Ukraine
Multiprofile Hospital for Active Treatment "Alexandrovska"
🇧🇬Sofia, Bulgaria
National Center for Heamtology and Transfusiology
🇧🇬Sofia, Bulgaria
Klinika Hematologii i Transplantacji Szpiku
🇵🇱Katowice, Poland
Klinika Hematologii Pomorskiej Akademii Medycznej w Szczecinie
🇵🇱Szczecin, Poland
Katedra i Klinika Hamatologii, Onkologii I Chorob Wewnetrznych AM
🇵🇱Warszawa, Poland
"Laikon" General Hospital, University of Athens
🇬🇷Goudi, Athens, Greece
State Healthcare Department "Sverdlovsk Regional Clinical Hospital #1",
🇷🇺Ekaterinburg,, Russian Federation
GOUVPO "Saint-Petersburg State Medical University named after acad I.P.Pavlov of Roszdrav", Bone Marrow Transplantology Clinic
🇷🇺Saint-Petersburg, Russian Federation
Donetsk State Medical University
🇺🇦Donetsk, Ukraine