• XmAb5574 is an Fc-engineered CD19 monoclonal antibody that is well tolerated as a single agent in patients with relapsed or refractory CLL.• XmAb5574 has preliminary efficacy as a single agent in CLL and is of interest for further study in this disease.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 Fcg 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. (Blood. 2014;124(24):3553-3560)

Lingual adenocarcinomas (ADC), either primary or metastatic to the tongue are extraordinarily rare neoplasms. Primary lingual adenocarcinomas are primarily of minor salivary gland origin. Two cases of primary colonic-type adenocarcinomas of the base of the tongue were recently reported for the first time in the English literature. We present an additional case of lingual intestinaltype adenocarcinoma with mucinous features that occurred in association with cervical node metastasis and discuss the clinicopathologic features and histogenetic aspects of this rare entity.

Polypoid lesions of the colon can be thought of to be under 3 broad categories: syndromic, mesenchymal, and epithelial.

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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.