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

Abstract

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.

Keywords: BI 836826; CD37; Diffuse large B cell lymphoma; Non-Hodgkin lymphoma; Phase I; Relapsed.

Conflict of interest statement

Frank Kroschinsky reports receiving reimbursement for costs of study treatments, documentation, congress fees and travel expenses from Boehringer Ingelheim. Jan Moritz Middeke declares that he has no conflict of interest. Martin Janz declares that he has no conflict of interest. Georg Lenz reports personal fees and/or research support from Amgen, AstraZeneca, BMS, Abbvie, Bayer, Janssen, Novartis, Gilead / Kite, Celgene, Roche, Takeda, Morphosys, ACERTA, AQUINOX, Agios, Verastem, NanoString, and Springer, outside the submitted work. Mathias Witzens-Harig declares that he has no conflict of interest. Reda Bouabdallah declares that he has no conflict of interest. Paul La Rosée reports personal fees from Boehringer Ingelheim (Travel support). Andreas Viardot reports personal fees and non-financial support from Roche, personal fees and non-financial support from Kite/Gilead, non-financial support from Abbvie, personal fees from Amgen, outside the submitted work. Gilles Salles reports personal fees from Amgen, BMS, Abbvie, Janssen, Merck, Novartis, Gilead / Kite, Epizyme, Pfizer, Celgene, Roche, Takeda, Autolus, MOrphosys, ACERTA, and Servier, outside the submitted work. Seok Jin Kim declares that he has no conflict of interest. Tae Min Kim declares that he has no conflict of interest. Oliver Ottmann declares that he has no conflict of interest. Joerg Chromik declares that he has no conflict of interest. Anne-Marie Quinson declares that he has no conflict of interest. Ute von Wangenheim and Ute Burkard are employees of Boehringer Ingelheim. Andreas Berk is an employee of ClinTriCare GmbH & Co. KG, contracted by Boehringer Ingelheim. Norbert Schmitz declares that he has no conflict of interest.

Figures

Fig. 1

Incidence and severity of infusion-related reactions over time

Fig. 2

Best percentage change from baseline in the sum of product of diameters (SPD) of the indicator lesions, based on imaging data