First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity

Abstract

Background: Bromodomain and extra-terminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC-or BRD4-driven diseases. A first-inhuman study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended Phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies. Material and methods: In this Phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose-response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated. Results: Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment. Conclusion: The study was prematurely terminated due to the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing 3 schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

“…Bromodomain and extra‐terminal (BET) proteins are epigenetic “readers” that recognize and bind posttranslational modifications on histones and other transcriptional machinery to facilitate gene expression. BET proteins have received an increasing amount of attention in recent years, 1–49 and BET inhibitor(s) (BETi) that target the BET bromodomains (BD) are unique in drug development in that they are consecutively undergoing clinical investigation in vastly different disease areas. Evidence is mounting to support the use of BETi in treating cancer, metabolic, inflammatory, neurologic, cardiovascular, and musculoskeletal diseases 1–3,14,19,20,29,31,44,50–62 .…”

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

“…Several BETis have already entered clinical trials, e.g. HMBA, OTX015 and ABBV-075 (21–23), but thus far the therapeutic effect of these inhibitors as monotherapies have been sparse. Our findings that MEK inhibitors, which are already available in clinical use, could synergize with BETis is therefore of clinical interest.…”

The emerging role of BET inhibitors in breast cancer

“…BAY 1238097 demonstrated preclinical activity in other solid tumors, including KRAS-mutated pancreatic ductal adenocarcinoma, KRAS-mutated NSCLC as well as melanoma [ 122 , 123 ]. A Phase I Dose Escalation Study was conducted to determine the maximum tolerated dose and safety profile of BAY 1238097 in advanced malignancies, other than breast cancer (NCT02369029) [ 124 ]. The study was prematurely terminated due to unexpected toxicity.…”

“…The study was prematurely terminated due to unexpected toxicity. All patients treated with BAY 1238097 discontinued from treatment due to either disease progression or adverse events [ 124 ]. One patient died from bilateral ischemic stroke not drug-related while two patients experienced DLTs including grade 3 headache and vomiting and Grade 2 nausea and back pain in doses below therapeutic threshold.…”