Clinical trial NCT00086580: Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients
Official title: A Phase III Randomized Trial to Evaluate the Efficacy and Safety of Second-Line Therapy With Fludarabine Plus Alemtuzumab vs. Fludarabine Alone in Patients With B-Cell Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: B-Cell Chronic Lymphocytic Leukemia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2004-07-08
Enrollment: 335
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment
timeFrame: Up to 6 years
Secondary outcomes:
measure: Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)
timeFrame: Up to 9 months
measure: Kaplan-Meier Estimates of Overall Survival Time
timeFrame: Up to 6 years
measure: Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)
timeFrame: Up to 6 years
measure: Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)
timeFrame: Up to 6 years
measure: Kaplan-Meier Estimates for Time to Alternative Therapy
timeFrame: Up to 6 years
measure: Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline
timeFrame: Day 0 (baseline)
measure: Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment
timeFrame: up to month 6 (end of treatment)
measure: Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline
timeFrame: Day 0 (baseline)
measure: Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment
timeFrame: up to month 6 (end of treatment)
measure: Summary of Participants With Adverse Experiences (AEs)
timeFrame: Up to 6 years
measure: Mean Systemic Clearance (CL) of Fludarabine
timeFrame: 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)
measure: Total Volume of Distribution (Vss) of Fludarabine
timeFrame: 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)
measure: Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)
timeFrame: 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)
measure: Maximum Plasma Concentration (Cmax) of Fludarabine
timeFrame: 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)
measure: Participants With Minimal Residual Disease (MRD)
timeFrame: up to 9 months
Other outcomes:
measure: Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II
timeFrame: Up to 6 years
measure: Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV
timeFrame: Up to 6 years
measure: Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II
timeFrame: Up to 6 years
measure: Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV
timeFrame: Up to 6 years
Locations:
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Graz
country: Austria
facility: Medizinische Universitatsklinik Graz
city: Wien
country: Austria
facility: Universitat Wien AKH, Innere Medizin I
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski
city: Plovdiv
country: Bulgaria
facility: UMHAT St. Georgi, Hematology Clinic
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Alexandrovska"
city: Sofia
country: Bulgaria
facility: National Center for Heamtology and Transfusiology
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment, St. Marina
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Hopital Notre-Dame du CHUM
state: Quebec
city: Rijeka
country: Croatia
facility: Clinical Hospital Center Rijeka, Department of Haematology
city: Zagreb
country: Croatia
facility: Clinical Hospital Merkur
city: Zagreb
country: Croatia
facility: University Hospital Dubrava
city: Lille, Cedex
country: France
facility: CHRU - Hopital Claude Huriez
city: Berlin
country: Germany
facility: Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin
city: Berlin
country: Germany
facility: Charite Universitatsklinikum der Humboldt-Universitat zu Berlin
city: Koln
country: Germany
facility: Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin
city: Stuttgart
country: Germany
facility: Robert-Bosch Krankenhaus GmbH
city: Goudi
country: Greece
facility: "Laikon" General Hospital, University of Athens
state: Athens
city: Cantanzaro
country: Italy
facility: U.O. Oncologia Medica Azienda Ospedaliera "Pugliese-Ciaccio"
city: Milano
country: Italy
facility: Unita Operativa di Medicina Generale Reumatologia e Oncoematologia
city: Rome
country: Italy
facility: Istituto di Ematologia Dipartmento di Biotechnologie Celluari ed Ematologia, Universita di Roma "La Sapienza"
city: Katowice
country: Poland
facility: Klinika Hematologii i Transplantacji Szpiku
city: Lodz
country: Poland
facility: Klinika Hematologii AM
city: Szczecin
country: Poland
facility: Klinika Hematologii Pomorskiej Akademii Medycznej w Szczecinie
city: Warszawa
country: Poland
facility: Katedra i Klinika Hamatologii, Onkologii I Chorob Wewnetrznych AM
city: Wroclaw
country: Poland
facility: Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria Servico de Hematologia Clinica/Hospital de dia de Hematologia
city: Viseu
country: Portugal
facility: Hospital de Sao Teotonio, Servico de Hematologia/Hosptial de Dia Oncologico
city: Bucharest
country: Romania
facility: Institutol Clinic Fundeni, Clinica Heamtologie
city: Ekaterinburg,
country: Russian Federation
facility: State Healthcare Department "Sverdlovsk Regional Clinical Hospital #1",
city: Moscow
country: Russian Federation
facility: GU "Main Military Clinical Hospital named after acad. N.N.Burdenko of MO of Russia", Haematology Centre 3
city: Saint-Petersburg
country: Russian Federation
facility: GOUVPO "Saint-Petersburg State Medical University named after acad I.P.Pavlov of Roszdrav", Bone Marrow Transplantology Clinic
city: Saint-Petersburg
country: Russian Federation
facility: Saint-Petersburg GUZ "City Hospital #31" 3, Dynamo Prospect
city: Lund
country: Sweden
facility: University Hospital, Dept. of Hematology
city: Orebro
country: Sweden
facility: Orebro University Hospital, Dep. of Medicine
city: Orebro
country: Sweden
facility: Universitetssjukhuset
city: Sundsvall
country: Sweden
facility: Medicin kliniken/Hematologsektionen
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset
city: Cherkasy
country: Ukraine
facility: Cherkasskly Oncology Dispensary
city: Dnepropetrovsk
country: Ukraine
facility: City Clinical Hospital #4, Regional Hematology Center
city: Donetsk
country: Ukraine
facility: Donetsk State Medical University
city: Kharkov
country: Ukraine
facility: Kharkov Regional Clinical Oncology Center, Department of Hematology
city: Khmelnitskiy
country: Ukraine
facility: Khmelnitskiy Regional Hospital, Hematology Department
city: Kiev
country: Ukraine
facility: Institute of Oncology AMS of Ukraine
city: Kiev
country: Ukraine
facility: Institute of Hematology and Transfusiology AMS of Ukraine, City Clinical Hospital #9
city: Kyiv
country: Ukraine
facility: Scientific Centre for Radiation Medicine AMS of Ukraine, Dept of Hematology and Transplantology
city: Lviv
country: Ukraine
facility: Lviv National Medical University named Danilo Galytcky
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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
citation: 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
citation: 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
citation: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemien S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. doi: 10.1016/S1470-2045(11)70242-X. Epub 2011 Oct 10.