Abstract B171: PK/PD modeling of the first-in-class, potent and selective covalent CDK7 inhibitor, SY-1365, provides mechanistic basis for intermittent dosing regimens in preclinical efficacy models of hematologic and solid tumors
Authors: Waters Nigel J. , Hu Shanhu , Matzuka Brett , Hodgson Graeme , Ren Yixuan , Choi Yoon , Dykstra Kevin , Roberts Christopher , Sprott Kevin , di Tomaso Emmanuelle , Fritz Christian 
Published: August 2018

Abstract
Introduction: CDK7 has recently emerged as an attractive gene control target in cancers driven by transcriptional dependencies, including triple-negative breast cancer (TNBC) and acute myeloid leukemia (AML). SY-1365 is a first-in-class, potent, and selective covalent CDK7 inhibitor that has shown durable and complete responses in xenograft models of AML and various solid tumors. To advance the development of this CDK7 inhibitor in patients, the current work assessed the relationship between SY-1365 pharmacokinetics (PK), pharmacodynamics (PD) measured as CDK7 target occupancy, and efficacy in mouse xenograft models of AML (HL-60) and TNBC (HCC70). Methods: SY-1365 was dosed intravenously in several xenograft experiments across a range of dose levels (5-40 mg/kg) and dose frequencies (daily to weekly). PK and changes in CDK7 occupancy were measured following single and repeat dosing, and efficacy studies measured the resultant dose-dependent changes in tumor volume over time after repeat dosing of SY-1365. To account for the temporal differences in PK, PD and tumor growth inhibition (TGI), a mathematical modeling approach was taken to integrate the resulting datasets. In addition, an assay to determine CDK7 occupancy in human PBMCs was developed to support the ongoing phase 1 study. Results: The PK in mouse was proportional with respect to dose and exhibited a terminal elimination half-life (t1/2) of 4 h. The PK/PD model was able to describe the PK, PD, and efficacy in HL-60 and HCC70 xenografts, with similar exposure and CDK7 occupancy profiles observed in these two xenografts. The model demonstrated a CDK7 turnover t1/2 of 69 h, longer than that reported for other oncogenic kinases targeted with covalent inhibitors where daily dosing is required (e.g., EGFRi, BTKi), with optimal efficacy achieved when target engagement was sustained over the dosing interval. This provides a mechanistic basis for intermittent dosing based on the dose-dependent TGI, including tumor regressions, observed with SY-1365 in in vivo models of TNBC and AML. Conclusions: The PK/PD relationship for target engagement and efficacy of the first-in-class potent and selective covalent CDK7 inhibitor, SY-1365, has been characterized in preclinical models through a mathematical modeling approach. Assays were developed to enable target occupancy quantification in xenograft tumors, and in human PBMCs as a surrogate tissue to support clinical investigation. Further investigations into tumor molecular profiles driving response are currently under way. In summary, this work supported the selection of an initial twice-weekly dosing regimen in the ongoing phase 1 trial of SY-1365 in adult patients with advanced solid tumors (NCT03134638).
Citation Format: Nigel J. Waters, Shanhu Hu, Brett Matzuka, Graeme Hodgson, Yixuan Ren, Yoon Choi, Kevin Dykstra, Christopher Roberts, Kevin Sprott, Emmanuelle di Tomaso, Christian Fritz. PK/PD modeling of the first-in-class, potent and selective covalent CDK7 inhibitor, SY-1365, provides mechanistic basis for intermittent dosing regimens in preclinical efficacy models of hematologic and solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B171.