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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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B-Cell Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: FluCAM [Fludara + Campath]
* Biological: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Arm (FluCAM)<br> | Biological: FluCAM [Fludara + Campath]<br>* 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.<br>* Other names: Campath;|
| Active Comparator: Fludarabine Alone<br> | Biological: fludarabine phosphate<br>* 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.<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 |