Abstract CT104: A first-in-human phase I dose escalation study of BET inhibitor GSK2820151 in patients with advanced or recurrent solid tumors cancers
Authors: Gadgeel Shirish , Keedy Vicki , Taylor Simon , Amin Khalid , Horner Thierry , Wu Yuehui , Prinjha Rab , Dhar Arindam , Kremer Brandon 
Published: July 2017

Abstract
Background
The Bromodomain (BRD) Extra Terminal (BET) family of proteins (BRD2, 3, 4 and T) contain bromodomains that recognize and bind acetylated histone tails. Binding affects chromatin structure facilitating recruitment of transcriptional complexes to specific genes regulating gene expression and mRNA elongation in a context and signal dependent fashion. BET proteins are involved in regulating transcription, cell growth and survival. Inhibiting BET protein binding to chromatin decreases expression of growth promoting genes and blocks both expression and transcriptional functions of MYC resulting in significant antitumor effects.
GSK2820151 is a potent and selective small molecule BET inhibitor. In preclinical studies, GSK2820151 potently inhibited proliferation of several solid tumor cell types in culture and demonstrated efficacy in xenograft models. These data plus understanding derived from the clinical progression of the BET inhibitor GSK525762 in solid (NCT01587703) and hematological (NCT01943851) tumors form the rationale for investigating the therapeutic potential of this structurally differentiated molecule GSK2820151 in a broad array of solid tumor types in this study.
Methods
201893 is a first-time in human phase I open-label, dose escalation study to investigate the maximum tolerated dose (MTD) and a recommended phase 2 dose (RP2D) based on the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of orally administered GSK2820151 in patients with solid tumors. This study will utilize an accelerated dose titration followed by a conventional 3+3 dose escalation phase to achieve MTD. The dose will be escalated based on PK data, the safety profile of prior cohorts, as well as the predicted dose-limiting toxicity (DLT) rates on all potential doses from the Neuenschwander Continual Reassessment Method (N-CRM) analysis. This is a single-arm study in which all subjects will receive GSK2820151 and will continue treatment until disease progression, unacceptable toxicity, or withdrawal of consent. A subject will be considered to have completed the study 2 years after the last treatment or if the subject dies or is still in follow-up at the time the study is closed or terminated, whichever is sooner. Approximately 30-50 patients will be enrolled. The study population will be adults, with advanced or recurrent, histologically or cytologically confirmed, solid malignancy that is either metastatic or unresectable, who either:
o refuse or are not candidates for standard curative or palliative therapy,
o have a disease for which no non-investigational therapy exists, OR
o have progressed on prior therapy Trial is opened to recruitment and as of January 12, 2017 one patient has been enrolled in the study. The trial is continuing as planned, results will be presented at a later date.
ClinicalTrials.gov identifier: NCT02630251
Study is funded by GlaxoSmithKline
Citation Format: Shirish Gadgeel, Vicki Keedy, Simon Taylor, Khalid Amin, Thierry Horner, Yuehui Wu, Rab Prinjha, Arindam Dhar, Brandon Kremer. A first-in-human phase I dose escalation study of BET inhibitor GSK2820151 in patients with advanced or recurrent solid tumors cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2017-CT104