Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of 
CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity 
(ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic 
lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled 
on five different dose cohorts administered weekly for 4 weeks. The maximally 
tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 
mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and 
lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean 
duration of 76 days, range 29-504 days) and one patient had a nodular partial 
response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at 
all doses post-treatment but also persisted at trough time points in the 3.0 
mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 
h following the first infusion, and 124 h following the fourth infusion. In 
summary, lucatumumab had acceptable tolerability, pharmacokinetics that 
supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 
mg/kg, but demonstrated minimal single-agent activity. Future efforts with 
lucatumumab in CLL should focus on combination-based therapy.