Final Results and Follow-up of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (aka MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Authors: Woyach Jennifer A. , Awan Farrukh , Flinn Ian , Berdeja Jesus G. , Wiley Elizabeth A , Mansoor Sharmeen , Huang Ying , Lozanski Gerard , Foster Paul A. , Byrd John C. 
Published: October 2019

Abstract
CD19 is an attractive target in lymphoid malignancies as it is highly expressed in nearly all CLL and non-Hodgkin’s lymphomas. While development of CD19 directed antibodies (abs) had previously been limited by antigen internalization, improved ab modification technology has restored this potential target. XmAb5574 (MOR00208) is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. We have previously presented safety and efficacy data from a first in human trial of this ab in relapsed or refractory (R/R) CLL, and now update these results along with results of a maintenance therapy cohort, follow-up efficacy data on all patients (pts), and correlative studies.
This study was a multi-institutional phase I trial of XmAb5574 in pts with R/R CLL. An accelerated titration design was used, with dose levels of 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the maximal tolerated dose (MTD). Patients received 9 intravenous infusions of XmAb5574: days 1, 4, 8, 15, and 22 of cycle 1, and days 1, 8, 15, and 22 of cycle 2. Once 5 patients were treated in the maximal dose cohort, additional patients who had at least stable disease after 2 cycles had the option to receive Xmab5574 every 28 days for an additional 4 infusions. Toxicity was assessed using the National Cancer Institute’s Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of Cycle 2. CT assessment was performed C2D28.
27 pts were enrolled, with a median age of 66 years (range 40-84). The pts were generally high risk: 14 had high-risk disease by Rai stage, 8 had del(11q22.3) and 10 had del(17p13.1) by FISH, and 24 had IgVH unmutated disease. The median number of prior therapies was 4 (range 1-13). Toxicity with this agent was modest with no MTD identified. 5 pts experienced grade 3 or 4 treatment-related toxicity, which included neutropenia (3 pts), thrombocytopenia (2 pts), increased aspartate aminotransferase (AST; 1 pt), febrile neutropenia (1 pt), and tumor lysis syndrome (1 pt). Grade 1 and 2 toxicities assessed as possibly related to XmAb5574 that occurred in more than 10% of pts included infusion reactions, increased AST, increased alanine aminotransferase, neutropenia, thrombocytopenia, fever, chills, and peripheral neuropathy. Infusion reactions occurred in 67% of patients, however, all were grade 1 or 2, and no reactions were seen following the first infusion.
On the basis of physical exam and laboratory studies, 18 patients (66.7%) achieved a partial response (PR), and the remaining 9 patients (33.3%) achieved stable disease (SD). Adding CT criteria, 8 patients (29.6%) achieved a PR with an additional 16 patients (59.3%) achieving SD. Two patients had progressive disease by CT criteria. No patient dosed below 3 mg/kg had an objective response. Of the 16 pts treated at the maximum dose, 12 patients (75%) had a PR by physical exam criteria and 6 patients (37.5%) had a PR by CT criteria, with 2 of these pts achieving a PR during the maintenance phase. Median progression free survival (PFS) for all patients was 199 days (95% CI: 168-299 days). For patients on all dose levels who received 9 doses or less, PFS was 189 days, and for the 8 patients on the extended treatment cohort, PFS was 420 days (95% CI: 168 days-not reached).
Flow cytometry was performed for absolute T and NK cell counts as well as activation. During the first 12 weeks, there was no significant change in T or NK cell counts; however, from cycle 1 day 1 pre to end of infusion there was a significant decrease in both T and NK cell number. There was no significant change in T or NK cell activation at any point.
PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. A steady-state was reached at or before infusion 9.
In conclusion, this Phase I trial demonstrates safety and preliminary efficacy of a novel Fc engineered CD19 monoclonal antibody XmAb5574 (MOR00208) and justifies movement into the Phase II setting. The modest toxicity combined with preliminary efficacy as a single agent will likely allow for successful combination therapies, and current studies in CLL are investigating XmAb5574 in combination with other active agents.

Disclosures
Foster: Xencor, Inc: Employment.