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

• ClinicalTrials.gov Identifier: NCT00086580
• Recruitment Status: Completed
• First Posted: July 8, 2004
• Results First Posted: August 11, 2011
• Last Update Posted: March 13, 2014
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
B-Cell Chronic Lymphocytic Leukemia	Biological: FluCAM [Fludara + Campath]; Biological: fludarabine phosphate	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 335 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: July 2004
• Actual Primary Completion Date: June 2010
• Actual Study Completion Date: June 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combination Arm (FluCAM)	Biological: 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.; Other Names: alemtuzumab; fludarabine phosphate; Fludara; Campath
Active Comparator: Fludarabine Alone	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.; Other Name: Fludara

Outcome Measures

Primary Outcome Measures :

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

1. Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) [ Time Frame: 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.
2. Kaplan-Meier Estimates of Overall Survival Time [ Time Frame: 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.
3. Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) [ Time Frame: 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.
4. Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) [ Time Frame: 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.
5. Kaplan-Meier Estimates for Time to Alternative Therapy [ Time Frame: 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.
6. Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline [ Time Frame: 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).
7. Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment [ Time Frame: 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).
8. Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline [ Time Frame: 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.
9. 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) ]
   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.
10. Summary of Participants With Adverse Experiences (AEs) [ Time Frame: 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.
11. 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) ]
    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.
12. 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) ]
    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.
13. 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) ]
    AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau).
14. 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) ]
    Cmax is the maximum plasma concentration of fludarabine observed.
15. Participants With Minimal Residual Disease (MRD) [ Time Frame: 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.

Other Outcome Measures:

1. 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 ]
   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 and include participants with Rai stage I or II.
2. 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 ]
   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 and include participants with Rai stage III or IV.
3. Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II [ Time Frame: 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 and include participants with Rai Stage I or II.
4. Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV [ Time Frame: 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 and include participants with Rai Stage III or IV.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Florida

Florida Cancer Specialists

Fort Myers, Florida, United States, 33916

Austria

Medizinische Universitatsklinik Graz

Graz, Austria, 8036

Universitat Wien AKH, Innere Medizin I

Wien, Austria, 1090

Bulgaria

University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski

Pleven, Bulgaria, 5800

UMHAT St. Georgi, Hematology Clinic

Plovdiv, Bulgaria, 4000

Multiprofile Hospital for Active Treatment "Alexandrovska"

Sofia, Bulgaria, 1431

National Center for Heamtology and Transfusiology

Sofia, Bulgaria, 1756

Multiprofile Hospital for Active Treatment, St. Marina

Varna, Bulgaria, 9010

Canada, Manitoba

Cancer Care Manitoba

Winnipeg, Manitoba, Canada, R3E 0V9

Canada, Quebec

Hopital Notre-Dame du CHUM

Montreal, Quebec, Canada, H2L 4M1

Croatia

Clinical Hospital Center Rijeka, Department of Haematology

Rijeka, Croatia, 51000

Clinical Hospital Merkur

Zagreb, Croatia, 10000

University Hospital Dubrava

Zagreb, Croatia, 10000

France

CHRU - Hopital Claude Huriez

Lille, Cedex, France, 59037

Germany

Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin

Berlin, Germany, 12203

Charite Universitatsklinikum der Humboldt-Universitat zu Berlin

Berlin, Germany, 13353

Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin

Koln, Germany, 50924

Robert-Bosch Krankenhaus GmbH

Stuttgart, Germany, 70376

Greece

"Laikon" General Hospital, University of Athens

Goudi, Athens, Greece, 11527

Italy

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

Cantanzaro, Italy, 88100

Unita Operativa di Medicina Generale Reumatologia e Oncoematologia

Milano, Italy, 20132

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

Rome, Italy, 00161

Poland

Klinika Hematologii i Transplantacji Szpiku

Katowice, Poland, 40-027

Klinika Hematologii AM

Lodz, Poland, 93-513

Klinika Hematologii Pomorskiej Akademii Medycznej w Szczecinie

Szczecin, Poland, 71-252

Katedra i Klinika Hamatologii, Onkologii I Chorob Wewnetrznych AM

Warszawa, Poland, 02-097

Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku

Wroclaw, Poland, 50-367

Portugal

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

Lisboa, Portugal, 1649-035

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

Viseu, Portugal, 3504-509

Romania

Institutol Clinic Fundeni, Clinica Heamtologie

Bucharest, Romania, 022328

Russian Federation

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

Ekaterinburg,, Russian Federation, 620102

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

Moscow, Russian Federation, 105229

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

Saint-Petersburg, Russian Federation, 197089

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

Saint-Petersburg, Russian Federation, 197110

Sweden

University Hospital, Dept. of Hematology

Lund, Sweden, 221 85

Orebro University Hospital, Dep. of Medicine

Orebro, Sweden, 701 85

Universitetssjukhuset

Orebro, Sweden, 701 85

Medicin kliniken/Hematologsektionen

Sundsvall, Sweden, 851 86

Akademiska sjukhuset

Uppsala, Sweden, 751 85

Ukraine

Cherkasskly Oncology Dispensary

Cherkasy, Ukraine, 79044

City Clinical Hospital #4, Regional Hematology Center

Dnepropetrovsk, Ukraine, 49102

Donetsk State Medical University

Donetsk, Ukraine, 83045

Kharkov Regional Clinical Oncology Center, Department of Hematology

Kharkov, Ukraine, 61070

Khmelnitskiy Regional Hospital, Hematology Department

Khmelnitskiy, Ukraine, 29000

Institute of Oncology AMS of Ukraine

Kiev, Ukraine, 03022

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

Kiev, Ukraine, 04112

Scientific Centre for Radiation Medicine AMS of Ukraine, Dept of Hematology and Transplantology

Kyiv, Ukraine, 03115

Lviv National Medical University named Danilo Galytcky

Lviv, Ukraine, 79044

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

More Information

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):

Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień 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.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00086580
• Other Study ID Numbers: CAM314; 2004-000149-39 ( EudraCT Number )
• First Posted: July 8, 2004
• Results First Posted: August 11, 2011
• Last Update Posted: March 13, 2014
• Last Verified: February 2014

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Vidarabine; Fludarabine; Fludarabine phosphate; Alemtuzumab; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antiviral Agents; Anti-Infective Agents; Antineoplastic Agents, Immunological