Summary
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 original version of this article unfortunately contained an error. In the Conflict of interest statement, Anne-Marie Quinson is described as declaring no conflict of interest.
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
14
C-BI 425809 30 µg. In study 2, participants received an oral dose of
14
C-BI 425809 25 mg containing
14
C-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
14
C-BI 425809 was 96.7%, with ~ 48% of
14
C-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
14
C-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.
Abstract only
2504
Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and ...selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting >4 cycles. C
max
and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T
1/2
was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting >4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.
Background and objectives
Photodynamic treatment with methylene blue (MB) and visible light is a well‐established pathogen inactivation system for human plasma. This technique is routinely used in ...different countries. MB/light treatment was shown to inactivate several transfusion‐transmittable viruses, but its efficiency for the inactivation of the quasi‐enveloped hepatitis E virus (HEV) has not yet been investigated.
Materials and methods
Plasma units were spiked with cell culture‐derived HEV and treated with the THERAFLEX MB‐Plasma system using various light doses (30, 60, 90, and 120 J/cm2). HEV titers in pre‐ and post‐treatment samples were determined by virus titration and a large‐volume plating assay to improve the detection limit of the virus assay.
Results
THERAFLEX MB‐Plasma efficiently inactivated HEV in human plasma. Even the lowest light dose of 30 J/cm2 inactivated HEV down to the limit of detection, with a mean log reduction factor of greater than 2.4 for the total process.
Conclusion
Our study demonstrates that the THERAFLEX MB‐Plasma system effectively inactivates HEV in human plasma.
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