Pharmacokinetics of Single-Agent Lumiliximab (Anti-CD23 Antibody) in Patients with Chronic Lymphocytic Leukemia.

Abstract

CD23 is highly expressed on the cell surface of certain B-cell malignancies including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this 46 patient, Phase I, multicenter study, single-agent L-mab was evaluated as a treatment for patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Pharmacokinetics (PK) and pharmacodynamic measurements were evaluated in patients with adequate data. L-mab and anti-L-mab antibody concentrations in plasma were measured by ELISA. L-mab coating of CLL cells and CD23 density on CLL cells were evaluated by flow cytometry. The absence of sustained L-mab concentrations did not allow PK calculations at the 125 mg/m2/wk and 250 mg/m2/wk dose levels. Doses at 375 mg/m2/wk or higher resulted in coating of CD23 binding sites on CLL cells and saturable PK (see table). Anti-L-mab antibody formation was not detected. CD23 density on CLL cells did not change during or after L-mab treatment. In summary, L-mab exhibits saturable PK, low clearance, and low volume of distribution without an immunogenic response. No down regulation of CD23 expression was observed on CLL cells in any dose group, and complete coating of CD23 sites was observed. Median Pharmacokinetic Parameters Treatment Group n C max(μ g/mL) Clearance (mL/m2/day) Volume of Distribution (mL/m2) Half-life (days) 1 3 39 - - - 2 3 84 - - - 3 8 180 310 3.02 7.9 4 9 245 335 3.22 7.3 5 8 430 406 3.45 5.4 6 9 654 293 3.58 10.6

Targeted treatment for chronic lymphocytic leukemia

“…In a phase I trial for patients with relapsed CLL, lumiliximab demonstrated decrease in lymphocyte counts in 91% of patients and reduction in lymphadenopathy in 59% of patients. 66 This was followed by a phase I/II trial in which lumiliximab was given in combination with the FCR regimen to patients with relapsed CLL. 67 This study enrolled 31 patients and lumiliximab was administered at 375 mg/m 2 (n = 3) or 500 mg/m 2 (n = 28) in combination with FCR for six cycles.…”