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

Genzyme, a Sanofi Company335 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

335

Conditions

B-Cell Chronic Lymphocytic Leukemia

Interventions

FluCAM [Fludara + Campath]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 phosphateBIOLOGICAL

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (48)

Outcomes

Primary Outcomes

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.

Time frame: Up to 6 years

Secondary Outcomes

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.

Time frame: Up to 9 months

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.

Time frame: Up to 6 years

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.

Time frame: Up to 6 years

Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)

Data from ClinicalTrials.gov

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