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.

© 2014 by The American Society of Hematology.

Figures

Figure 1

Change in lymphocyte count from baseline. The lowest lymphocyte count for each patient during the observation period was compared with baseline.

Figure 2

Change in B-cell counts during therapy. B cells were characterized using CD5, CD19, CD24, CD43, and CD79b. After XmAb5574, CD19 was not detectable, so CD24 was primarily used to identify B cells. No patient had >1% normal B cells, so all CD24+ cells were determined to be CLL cells. Over the course of therapy, CLL cell count decreased significantly (P = .01), with lowest level seen at the end of therapy.

Figure 3

Best change in sum of product of lymph nodes. Physical examination (A) or CT (B). Physical examination, including lymph node measurement, was performed at the time of each infusion and then at 4, 8, and 12 weeks postinfusion. CT scans were obtained on cycle 2, day 28.

Figure 4

PFS. PFS by Kaplan-Meier method is shown for all patients (A), those who received up to 9 doses on all dose levels (B), and those who were included in the extended dosing cohort (C).