title: A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma.
abstract: In this open-label, multicentre, phase 1 study a fully human anti-CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty-eight patients, enrolled using a standard '3 + 3' dose escalation, received one or two (n = 3) cycles of lucatumumab 1·0, 3·0, 4·5 or 6·0 mg/kg once weekly for 4 weeks. Common lucatumumab-related adverse events were reversible, mild-to-moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4·5 mg/kg. At doses ≥3·0 mg/kg, sustained receptor occupancy (≥87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half-life of 4-19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ≥8 months. These findings indicate that single-agent lucatumumab was well tolerated up to 4·5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA 98109-1024, USA. wbensing@fhcrc.org
authors.forename: William
authors.initials: W
authors.lastname: Bensinger
authors.forename: Richard T
authors.initials: RT
authors.lastname: Maziarz
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Becker
authors.forename: Brett
authors.initials: B
authors.lastname: Ewald
authors.forename: Sanela
authors.initials: S
authors.lastname: Bilic
authors.forename: John
authors.initials: J
authors.lastname: Rediske
authors.forename: Johan
authors.initials: J
authors.lastname: Baeck
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D012008:Recurrence
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C578314:lucatumumab