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

B-Cell Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00086580
• Other study ID #: CAM314
• Secondary ID: 2004-000149-39
• Status: Completed
• Phase: Phase 3
• First received: July 6, 2004
• Last updated: February 10, 2014
• Start date: July 2004
• Est. completion date: June 2010

Study information

• Verified date: February 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustria: Federal Ministry for Health and WomenBulgaria: Bulgarian Drug AgencyCanada: Health CanadaCroatia: Ministry of Health and Social CareCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: National Organization of MedicinesItaly: Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPortugal: National Pharmacy and Medicines InstituteRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSweden: Medical Products AgencyUkraine: State Pharmacological Center - Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 335
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• B-Cell Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

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.
• 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.

Locations

Country	Name	City	State
Austria	Medizinische Universitatsklinik Graz	Graz
Austria	Universitat Wien AKH, Innere Medizin I	Wien
Bulgaria	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
Canada	Hopital Notre-Dame du CHUM	Montreal	Quebec
Canada	Cancer Care Manitoba	Winnipeg	Manitoba
Croatia	Clinical Hospital Center Rijeka, Department of Haematology	Rijeka
Croatia	Clinical Hospital Merkur	Zagreb
Croatia	University Hospital Dubrava	Zagreb
France	CHRU - Hopital Claude Huriez	Lille, Cedex
Germany	Charite Universitatsklinikum der Humboldt-Universitat zu Berlin	Berlin
Germany	Charite-Universitatsmedizin Berlin Campus Benjamin-Franklin	Berlin
Germany	Klinikum der Universitat zu Koln, Klinik 1 fur Innere Medizin	Koln
Germany	Robert-Bosch Krankenhaus GmbH	Stuttgart
Greece	"Laikon" General Hospital, University of Athens	Goudi	Athens
Italy	U.O. Oncologia Medica Azienda Ospedaliera "Pugliese-Ciaccio"	Cantanzaro
Italy	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
Poland	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	Warszawa
Poland	Klinika Hematologii, Nowotworow Krwii 1 Transplantacji Szpiku	Wroclaw
Portugal	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
Romania	Institutol Clinic Fundeni, Clinica Heamtologie	Bucharest
Russian Federation	State Healthcare Department "Sverdlovsk Regional Clinical Hospital #1",	Ekaterinburg,
Russian Federation	GU "Main Military Clinical Hospital named after acad. N.N.Burdenko of MO of Russia", Haematology Centre 3	Moscow
Russian Federation	GOUVPO "Saint-Petersburg State Medical University named after acad I.P.Pavlov of Roszdrav", Bone Marrow Transplantology Clinic	Saint-Petersburg
Russian Federation	Saint-Petersburg GUZ "City Hospital #31" 3, Dynamo Prospect	Saint-Petersburg
Sweden	University Hospital, Dept. of Hematology	Lund
Sweden	Orebro University Hospital, Dep. of Medicine	Orebro
Sweden	Universitetssjukhuset	Orebro
Sweden	Medicin kliniken/Hematologsektionen	Sundsvall
Sweden	Akademiska sjukhuset	Uppsala
Ukraine	Cherkasskly Oncology Dispensary	Cherkasy
Ukraine	City Clinical Hospital #4, Regional Hematology Center	Dnepropetrovsk
Ukraine	Donetsk State Medical University	Donetsk
Ukraine	Kharkov Regional Clinical Oncology Center, Department of Hematology	Kharkov
Ukraine	Khmelnitskiy Regional Hospital, Hematology Department	Khmelnitskiy
Ukraine	Institute of Hematology and Transfusiology AMS of Ukraine, City Clinical Hospital #9	Kiev
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
United States	Florida Cancer Specialists	Fort Myers	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Canada,  Croatia,  France,  Germany,  Greece,  Italy,  Poland,  Portugal,  Romania,  Russian Federation,  Sweden,  Ukraine, 

References & Publications (3)

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 Hematolo

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

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II	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.	Up to 6 years	No
Other	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV	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.	Up to 6 years	No
Other	Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II	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.	Up to 6 years	No
Other	Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV	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.	Up to 6 years	No
Primary	Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment	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.	Up to 6 years	No
Secondary	Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)	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.	Up to 9 months	No
Secondary	Kaplan-Meier Estimates of Overall Survival Time	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.	Up to 6 years	No
Secondary	Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)	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.	Up to 6 years	No
Secondary	Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)	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.	Up to 6 years	No
Secondary	Kaplan-Meier Estimates for Time to Alternative Therapy	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.	Up to 6 years	No
Secondary	Mean EQ-5D™ Index Scores to Measure Quality of Life at 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).	Day 0 (baseline)	No
Secondary	Mean EQ-5D™ Index Scores to Measure Quality of Life at 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).	up to month 6 (end of treatment)	No
Secondary	Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at 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.	Day 0 (baseline)	No
Secondary	Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at 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.	up to month 6 (end of treatment)	No
Secondary	Summary of Participants With Adverse Experiences (AEs)	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.	Up to 6 years	Yes
Secondary	Mean Systemic Clearance (CL) of Fludarabine	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.	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)	No
Secondary	Total Volume of Distribution (Vss) of Fludarabine	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.	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)	No
Secondary	Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)	AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (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)	No
Secondary	Maximum Plasma Concentration (Cmax) of Fludarabine	Cmax is the maximum plasma concentration of fludarabine observed.	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)	No
Secondary	Participants With Minimal Residual Disease (MRD)	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.	up to 9 months	No