title: A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma.
abstract: This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R St, Detroit, MI 48201, USA. zonderj@karmanos.org
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Zonder
authors.forename: Ann F
authors.initials: AF
authors.lastname: Mohrbacher
authors.forename: Seema
authors.initials: S
authors.lastname: Singhal
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: William I
authors.initials: WI
authors.lastname: Bensinger
authors.forename: Han
authors.initials: H
authors.lastname: Ding
authors.forename: John
authors.initials: J
authors.lastname: Fry
authors.forename: Daniel E H
authors.initials: DE
authors.lastname: Afar
authors.forename: Anil K
authors.initials: AK
authors.lastname: Singhal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C546027:elotuzumab