A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors

Abstract

SummaryPurpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4–130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48 %). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20 %), neutropenia, alopecia (16 % each), anemia, dry skin, and nausea (12 % each). Treatment-related grade ≥3 AEs were neutropenia (12 %), anemia (8 %), and febrile neutropenia (4 %); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4 %; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients’ solid tumors.

AMG 595, an Anti-EGFRvIII Antibody–Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma

“…No dose response was observed with AMG 595 treatment; however, the dynamic range of the assay was merely 2-fold; to improve the sensitivity of the assay further, optimization of the assay itself and the collection time are likely required. Recent clinical studies testing aurora kinase inhibitors included exploratory pharmacodynamic endpoints to assess phospho-histone H3 levels in normal skin (40,41). Preclinical efficacy has been observed with several conjugates, whereas translation into the clinic based on a maximally effective minimal dose has been difficult to determine due largely to the lack of pharmacodynamic markers that can be employed in preclinical and clinical studies.…”

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

“…Another Aurora B kinase inhibitor, BI 831266, has also been recently studied in a phase I trial of patients with advanced solid tumors. Similar to the agent investigated in the current study, BI 831266 treatment resulted in objective response in only one patient (cervical cancer), with 16 % of patients experiencing SD [39]. The BI 831266 trial was discontinued based on these data, as well as the limited activity displayed by BI 811283 in this population.…”

Identification of Potent Inhibitors against Aurora Kinase A Using Molecular Docking and Molecular Dynamics Simulation Studies

“…The molecular docking was used to examine the binding interaction between the protein-ligand complexes [33][34][35][36]. The LCMS identified molecules were carried out by docking study in the binding site of 3H10 human protein using Glide SP and XP module (Glide, Schrödinger, LLC, New York, NY, 2018-3).…”

“…Studies report that these phytochemicals demonstrate different therapeutic effects, such as antimicrobial and antioxidants [24] and anti-nociceptive [25], antidiabetic [19,26], anticancer [27], wound-healing properties [28,29], having elastase, and collagenase [30], cyclooxygenase 2 [31], dipeptidyl peptidase-4 [32], PPAR-γ [33] and alpha-ketoglutarate dependent dioxygenase FTO inhibitory action [34]. Currently available aurora inhibitors namely ZM447439, Hesperadin, and VX-680 possess some side effects like alopecia, anemia, dry skin and toxicity on the bone marrow [35,36]. Therefore, there is an emerging need to find potent aurora inhibitors with low toxicity.…”