Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

The Absolute Bioavailability, Absorption, Distribution, Metabolism, and Excretion of BI 425809 Administered as an Oral Dose or an Oral Dose with an Intravenous Microtracer Dose of [14C]-BI 425809 in Healthy Males.

BACKGROUND AND OBJECTIVES: BI 425809, a novel glycine transporter-1 inhibitor, may ameliorate cognitive deficits in schizophrenia. The objectives of the studies were: to assess absolute bioavailability of oral BI 425809 compared with intravenous (IV) microtracer infusion (study 1), and to determine the mass balance, distribution, metabolism, and excretion of BI 425809 (study 2). METHODS: These were Phase I, open-label, non-randomized, single-period, single-arm studies in healthy males. Study 1 administered a single oral dose of unlabeled BI 425809 25 mg, then an IV microtracer infusion of [14C]-BI 425809 30 µg. In study 2, participants received an oral dose of [14C]-BI 425809 25 mg containing [14C]-labeled (dose: 3.7 megabecquerel (0.41 mSv)) and unlabeled drug. Safety was assessed. RESULTS: In study 1 (n = 6), the absolute bioavailability of a 25 mg tablet of BI 425809 in a fasted state was 71.64%. The geometric mean dose-normalized maximum plasma concentration was approximately 80% lower after oral administration versus IV dose. In study 2 (n = 6), the total recovery of [14C]-BI 425809 was 96.7%, with ~ 48% of [14C]-radioactivity excreted in urine and ~ 48% excreted in feces. Among the labeled drug in urine, ~ 45% of the amount excreted was composed of BI 425809 (17.4%) and two metabolites (BI 758790, 21.0%; BI 761036, 5.9%). In feces, < 1% of BI 425809 was excreted as unchanged drug. In both studies, BI 425809 was generally well tolerated. CONCLUSIONS: After normalization, the absolute bioavailability of tablet-form BI 425809 was 71.64%. The total recovery of [14C]-BI 425809 25 mg was high (96.7%), with low intraindividual variability and similar amounts excreted in urine and feces. CLINICALTRIALS. GOV IDENTIFIERS: NCT03783000 and NCT03654170.