Eculizumab in Treating Patients With Paroxysmal Nocturnal Hemoglobinuria

OBJECTIVES:

Primary

• Determine the safety of eculizumab in patients with transfusion-dependent hemolytic paroxysmal nocturnal hemoglobinuria.
• Determine the efficacy of this drug, in terms of hemoglobin stabilization and the number of packed red blood cell units transfused during the 26-week treatment period, in these patients.

Secondary

• Compare the occurrence of transfusion avoidance, hemolysis (measured by lactate dehydrogenase [LDH] area under the curve), and the changes in fatigue during the 26-week treatment period in patients treated with this drug vs placebo.
• Compare LDH changes, quality of life changes, thrombosis, platelet activity, nitric oxide, and free hemoglobin measures during the 26-week treatment period in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to the number of packed red blood cell (PRBC) units transfused 1 year prior to screening (< 15 units vs 15-25 units vs > 25 units). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Within 10 days after PRBC transfusion (administered during the study observation period), patients receive placebo IV over 30 minutes once a week for 5 weeks and then once every 2 weeks for 21 weeks.
• Arm II: Within 10 days after PRBC transfusion (administered during the study observation period), patients receive eculizumab IV over 30 minutes once a week for 5 weeks and then once every 2 weeks for 21 weeks.

Quality of life is assessed at baseline; at weeks 0-4, 12, 20, and 26 during study treatment; then at weeks 1, 2, 4, and 8 after completion of study treatment.

After completion of study treatment, patients are followed at weeks 1, 2, 4, and 8.

PROJECTED ACCRUAL: Approximately 75 patients (37 per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of paroxysmal nocturnal hemoglobinuria
• Must have required ≥ 4 episodes of transfusions for anemia or anemia-related symptoms within the past year

• Mean pre-transfusion hemoglobin ≤ 10. 5 g/dL over the past year
• Glycosylphosphatidylinositol (GPI)-deficient red blood cell clone (type III cells) of ≥ 10% by flow cytometry
• Must have received 1 packed red blood cell transfusion during the study observation period (within 48 hours of the hemoglobin level that precipitated the transfusion) and within 1.5 g/dL of the mean pre-transfusion hemoglobin level over the past year

• Pre-transfusion hemoglobin ≤ 9 g/dL with symptoms
• Pre-transfusion hemoglobin ≤ 7 g/dL without symptoms
• Received Neisseria meningitidis vaccination at least 2 weeks before initiation of study therapy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics
• Absolute neutrophil count > 500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Lactate dehydrogenase ≥ 1.5 times upper limit of normal

Renal

• Not specified

Immunologic

• No known or suspected active bacterial infection
• No recurrent bacterial infections
• No history of meningococcal disease

Other

• No known or suspected hereditary complement deficiency
• No other condition that would increase the patient's risk or confound the outcome of the study
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No prior bone marrow transplantation
• Concurrent epoetin alfa allowed*

Chemotherapy

• Not specified

Endocrine therapy

• Concurrent corticosteroids allowed**

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• More than 30 days since prior participation in another investigational drug trial
• More than 30 days since prior investigational agents, devices, or procedures
• Concurrent immunosuppressants allowed*
• Concurrent warfarin allowed provided INR level is stable for the past 4 weeks and expected to remain stable during observation and study treatment
• Concurrent iron supplements or folic acid allowed**
• Concurrent low-molecular weight heparin allowed** NOTE: *Provided dose is stable for the past 26 weeks and during study observation and treatment

NOTE: **Provided dose is stable for the past 4 weeks and expected to remain stable (or decrease for corticosteroids) during study observation and treatment