title: Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. john.byrd@osumc.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.forename: Maureen
authors.initials: M
authors.lastname: Cooper
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bendiske
authors.forename: John
authors.initials: J
authors.lastname: Rediske
authors.forename: Sanela
authors.initials: S
authors.lastname: Bilic
authors.forename: Jyotirmoy
authors.initials: J
authors.lastname: Dey
authors.forename: Johan
authors.initials: J
authors.lastname: Baeck
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; C578314:lucatumumab