Abstract 3674: Pharmacodynamic assessment in whole blood for the BET bromodomain inhibitor CPI-0610 of target engagement in patients with progressive lymphoma
Authors: Mertz Jennifer A. , Blum Kristie A. , Younes Anas , Abramson Jeremy S. , Maris Michael B. , Flinn Ian W. , Goy Andre , Borger Darrell R. , Cooper Michael R. , Sims Robert J. 
Published: August 2018

Abstract
Defining the relationship between small molecule exposure, clinical efficacy and target engagement via pharmacodynamic (PD) biomarkers is a key element of phase 1 clinical development. CPI-0610 is an orally bioavailable inhibitor of the bromodomain and extra-terminal (BET) domain family of proteins currently being evaluated in a number of phase I trials. To support the clinical development of CPI-0610, we sought to identify BET target genes in whole blood that function as PD markers for target engagement in patients. The utilization of whole blood rather than tumor samples for PD assessments allows for a high level of compliance for sample collection and assessment of serial samples to understand the kinetics of optimal gene regulation. This is important for the mechanism of action of BET bromodomain inhibitors, as it has been shown that target gene suppression is rapidly reversible upon removal of drug. A preliminary list of BET target genes was first identified after ex vivo treatment of healthy donor blood samples with a BET inhibitor followed by transcriptional profiling. Further characterization was carried out using blood samples recovered from in vivo studies in mice, as well as rat and dog toxicology studies for CPI-0610. Blood samples collected from patients with progressive lymphoma participating in a Phase I clinical study (NCT01949883) were analyzed for changes in the BET target genes and correlated with CPI-0610 dose, pharmacokinetic (PK) exposure and clinical activity. This enabled further refinement of the BET target gene signature to identify the most robust gene expression changes in patient samples. IL8 and CCR1 were the most strongly regulated genes, showing an exposure-dependent downregulation in patient samples. Using these target genes, we were able to identify a minimum threshold of exposure required for BET target engagement as well as show that BET target engagement can be achieved at doses below the maximum tolerated dose. Furthermore, ≥50% downregulation of IL8 was consistent with anti-lymphoma activity in patients from our trial. CCR2, FN1, CSF1R and THBS1 were identified and validated preclinically but in patient samples were difficult to interpret due to lack of robust regulation or low basal levels of expression. In summary, a BET target gene signature assay using whole blood samples was established and implemented in a Phase I lymphoma study which demonstrated that CPI-0610 regulates direct BET target genes in blood cells in a robust and dose-dependent manner.
Citation Format: Jennifer A. Mertz, Kristie A. Blum, Anas Younes, Jeremy S. Abramson, Michael B. Maris, Ian W. Flinn, Andre Goy, Darrell R. Borger, Michael R. Cooper, Robert J. Sims. Pharmacodynamic assessment in whole blood for the BET bromodomain inhibitor CPI-0610 of target engagement in patients with progressive lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3674.