title: A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL.
abstract: CD19 is ubiquitously expressed on chronic lymphocytic leukemia (CLL) cells and is therefore an attractive candidate for antibody targeting. XmAb5574 (aka MOR00208) is a novel humanized CD19 monoclonal antibody with an engineered Fc region to enhance Fcγ receptor binding affinity. Here we report results of a first in human phase 1 trial of XmAb5574 in patients with relapsed or refractory CLL. Twenty-seven patients were enrolled to 6 escalating dose levels, with expansion at the highest dose level of 12 mg/kg. Nine doses of XmAb5574 were infused over 8 weeks. No maximal tolerated dose was reached, and the drug was generally well tolerated, with infusion reactions of grades 1 and 2 being the most common toxicities. Grade 3 and 4 toxicities occurred in 5 patients and included neutropenia, thrombocytopenia, increased aspartate aminotransferase, febrile neutropenia, and tumor lysis syndrome. XmAb5574 showed preliminary efficacy, with 18 patients (66.7%) responding by physical examination criteria and laboratory studies, and 8 patients (29.6%) responding by computed tomography criteria. Pharmacokinetics showed a half-life of 14 days with clearance that was not dose-dependent. In conclusion, this phase 1 trial demonstrates safety and preliminary efficacy of a novel Fc-engineered CD19 monoclonal antibody XmAb5574 and justifies movement into the phase 2 setting. This trial was registered at www.clinicaltrials.gov as #NCT01161511.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Farrukh
authors.initials: F
authors.lastname: Awan
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN;
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN;
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Berdeja
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wiley
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH; and.
authors.forename: Sharmeen
authors.initials: S
authors.lastname: Mansoor
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Xencor, Inc., Monrovia, CA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D000912:Antibodies, Neoplasm / Q000008:administration & dosage*; D018941:Antigens, CD19; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000008:administration & dosage; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012008:Recurrence; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D007127:Immunoglobulin Constant Regions