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.
Eur J Cancer
; 109: 103-110, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30711772
BACKGROUND: Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human 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 because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Benzodiazepinas
/
Proteínas de Ciclo Celular
/
Resistencia a Antineoplásicos
/
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos
/
Neoplasias
Tipo de estudio:
Clinical_trials
/
Etiology_studies
/
Observational_studies
/
Prognostic_studies
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur J Cancer
Año:
2019
Tipo del documento:
Article