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

NCT ID: NCT00086580

Last Updated: 2014-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 335 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-07-31
• Study Completion Date: 2010-06-30

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.

Conditions

B-Cell Chronic Lymphocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Combination Arm (FluCAM)

Group Type: EXPERIMENTAL

FluCAM [Fludara + Campath]

Intervention Type: BIOLOGICAL

Phase A: Escalating Doses of alemtuzumab (Campath) Alone

Day 1: alemtuzumab 3 mg intravenously (IV) over 2 hours.

Day 2: alemtuzumab 10 mg IV over 2 hours if 3 mg was tolerated, else repeat 3 mg daily until tolerated.

Day 3: alemtuzumab 30 mg IV over 2 hours if 10 mg was tolerated, else repeat 10 mg daily until tolerated.

Participants were allowed 3-14 days to escalate to 30 mg. Once 30 mg was tolerated, the participant had to begin Phase B within 7 days.

Phase B: FluCAM

Cycle 1: Days 1,2,3 fludarabine phosphate administered at 30 mg/m^2 over 30 minutes IV, followed within 1 hour by alemtuzumab 30 mg IV over 2 hours. A similar schedule is set for Cycles 2 through 6; duration of alemtuzumab infusions vary from 2-6 hours. Each 28-day period is 1 cycle. Fludarabine phosphate dosage is based on participants' body surface area at the beginning of each cycle. FluCAM administered up to a maximum of 6 cycles, based upon participants' response to therapy and toxicity.

Fludarabine Alone

Group Type: ACTIVE_COMPARATOR

fludarabine phosphate

Intervention Type: BIOLOGICAL

Fludarabine phosphate (Fludara) is administered at a dose of 25 mg/m\^2 IV over 15 to 30 minutes daily for 5 consecutive days (days 1 through 5) every 28 days (per package instructions). Each 28-day period is 1 cycle. The dose of fludarabine phosphate will be based on the participant's body surface area as calculated at the beginning of each cycle. Participants treated with fludarabine phosphate up to a maximum of 6 cycles, based upon their response to therapy and toxicity.

Interventions

FluCAM [Fludara + Campath]

Phase A: Escalating Doses of alemtuzumab (Campath) Alone

Day 1: alemtuzumab 3 mg intravenously (IV) over 2 hours.

Day 2: alemtuzumab 10 mg IV over 2 hours if 3 mg was tolerated, else repeat 3 mg daily until tolerated.

Day 3: alemtuzumab 30 mg IV over 2 hours if 10 mg was tolerated, else repeat 10 mg daily until tolerated.

Participants were allowed 3-14 days to escalate to 30 mg. Once 30 mg was tolerated, the participant had to begin Phase B within 7 days.

Phase B: FluCAM

Cycle 1: Days 1,2,3 fludarabine phosphate administered at 30 mg/m^2 over 30 minutes IV, followed within 1 hour by alemtuzumab 30 mg IV over 2 hours. A similar schedule is set for Cycles 2 through 6; duration of alemtuzumab infusions vary from 2-6 hours. Each 28-day period is 1 cycle. Fludarabine phosphate dosage is based on participants' body surface area at the beginning of each cycle. FluCAM administered up to a maximum of 6 cycles, based upon participants' response to therapy and toxicity.

Intervention Type: BIOLOGICAL

fludarabine phosphate

Fludarabine phosphate (Fludara) is administered at a dose of 25 mg/m\^2 IV over 15 to 30 minutes daily for 5 consecutive days (days 1 through 5) every 28 days (per package instructions). Each 28-day period is 1 cycle. The dose of fludarabine phosphate will be based on the participant's body surface area as calculated at the beginning of each cycle. Participants treated with fludarabine phosphate up to a maximum of 6 cycles, based upon their response to therapy and toxicity.

Intervention Type: BIOLOGICAL

Other Intervention Names

alemtuzumab; fludarabine phosphate; Fludara; Campath; Fludara

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Genzyme, a Sanofi Company

Locations

Florida Cancer Specialists

Fort Myers, Florida, United States

Medizinische Universitatsklinik Graz

Graz, , Austria

Universitat Wien AKH, Innere Medizin I

Vienna, , Austria

University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski

Pleven, , Bulgaria

UMHAT St. Georgi, Hematology Clinic

Plovdiv, , Bulgaria

Multiprofile Hospital for Active Treatment "Alexandrovska"

Sofia, , Bulgaria

National Center for Heamtology and Transfusiology

Sofia, , Bulgaria

Multiprofile Hospital for Active Treatment, St. Marina

Varna, , Bulgaria

Cancer Care Manitoba

Winnipeg, Manitoba, Canada

Hopital Notre-Dame du CHUM

Montreal, Quebec, Canada

Clinical Hospital Center Rijeka, Department of Haematology

Rijeka, , Croatia

Clinical Hospital Merkur

Zagreb, , Croatia

University Hospital Dubrava

Zagreb, , Croatia

CHRU - Hopital Claude Huriez

Lille, , France

Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin

Berlin, , Germany

Charite Universitatsklinikum der Humboldt-Universitat zu Berlin

Berlin, , Germany

Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin

Cologne, , Germany

Robert-Bosch Krankenhaus GmbH

Stuttgart, , Germany

"Laikon" General Hospital, University of Athens

Goudi, Athens, Greece

U.O. Oncologia Medica Azienda Ospedaliera "Pugliese-Ciaccio"

Cantanzaro, , Italy

Unita Operativa di Medicina Generale Reumatologia e Oncoematologia

Milan, , Italy

Istituto di Ematologia Dipartmento di Biotechnologie Celluari ed Ematologia, Universita di Roma "La Sapienza"

Rome, , Italy

Klinika Hematologii i Transplantacji Szpiku

Katowice, , Poland

Klinika Hematologii AM

Lodz, , Poland

Klinika Hematologii Pomorskiej Akademii Medycznej w Szczecinie

Szczecin, , Poland

Katedra i Klinika Hamatologii, Onkologii I Chorob Wewnetrznych AM

Warsaw, , Poland

Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku

Wroclaw, , Poland

Hospital de Santa Maria Servico de Hematologia Clinica/Hospital de dia de Hematologia

Lisbon, , Portugal

Hospital de Sao Teotonio, Servico de Hematologia/Hosptial de Dia Oncologico

Viseu, , Portugal

Institutol Clinic Fundeni, Clinica Heamtologie

Bucharest, , Romania

GU "Main Military Clinical Hospital named after acad. N.N.Burdenko of MO of Russia", Haematology Centre 3

Moscow, , Russia

GOUVPO "Saint-Petersburg State Medical University named after acad I.P.Pavlov of Roszdrav", Bone Marrow Transplantology Clinic

Saint Petersburg, , Russia

Saint-Petersburg GUZ "City Hospital #31" 3, Dynamo Prospect

Saint Petersburg, , Russia

State Healthcare Department "Sverdlovsk Regional Clinical Hospital #1",

Yekaterinburg, , Russia

University Hospital, Dept. of Hematology

Lund, , Sweden

Orebro University Hospital, Dep. of Medicine

Örebro, , Sweden

Universitetssjukhuset

Örebro, , Sweden

Medicin kliniken/Hematologsektionen

Sundsvall, , Sweden

Akademiska sjukhuset

Uppsala, , Sweden

Cherkasskly Oncology Dispensary

Cherkasy, , Ukraine

City Clinical Hospital #4, Regional Hematology Center

Dnipro, , Ukraine

Donetsk State Medical University

Donetsk, , Ukraine

Kharkov Regional Clinical Oncology Center, Department of Hematology

Kharkiv, , Ukraine

Khmelnitskiy Regional Hospital, Hematology Department

Khmelnitskiy, , Ukraine

Institute of Oncology AMS of Ukraine

Kiev, , Ukraine

Institute of Hematology and Transfusiology AMS of Ukraine, City Clinical Hospital #9

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

Countries

United States; Austria; Bulgaria; Canada; Croatia; France; Germany; Greece; Italy; Poland; Portugal; Romania; Russia; Sweden; Ukraine

References

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

Reference Type: RESULT

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

Reference Type: RESULT

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

Reference Type: RESULT

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.

Reference Type: DERIVED

PMID: 21992852 (View on PubMed)

Other Identifiers

2004-000149-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CAM314

Identifier Type: -

Identifier Source: org_study_id