Abstract 14P
Background
Selective CDK7 inhibition has been shown to target two fundamental processes in cancer: transcription and cell cycle control. SY-5609 is a potent and selective CDK7 inhibitor in Ph1 clinical development in patients with advanced solid tumors including ovarian cancer (NCT04247126). Here we report on the impact of intermittent SY-5609 dosing regimens on tumor growth inhibition (TGI), pharmacodynamic (PD) activity, and pharmacokinetics (PK) in a xenograft model of high grade serous ovarian cancer (HGSOC).
Methods
TGI was compared in OVCAR3 xenografts across a range of SY-5609 doses (1, 3, 6 mpk) and schedules (continuous daily [QD], 5d per wk [5/2], and 7d per wk every other wk [7/7]), and the same total daily dose was evaluated twice daily (BID) vs QD on a continuous schedule. Steady state tumor PK and PD (POLR2A and E2F1 expression) were assessed 8-72 hours after the 5th QD dose in separate mice.
Results
SY-5609 induced dose dependent TGI across all dosing regimens. Higher doses on 5/2 and 7/7 schedules led to TGI or regressions consistent with lower doses given QD. SY-5609 dose-dependent changes in tumor PD markers were sustained above baseline for up to 72 hours. TGI was enhanced when the same total daily dose was administered BID versus QD. Evaluation of SY-5609 PK during BID and QD schedules demonstrated increased antitumor activity associated with maintenance of higher trough levels of SY-5609. All regimens were well tolerated with no body weight loss.
Conclusions
SY-5609 shows robust antitumor activity in preclinical HGSOC xenografts across schedules that integrate higher doses with dosing holidays, supported by sustained PD effects in tumor tissue after dose cessation. Enhanced SY-5609 antitumor activity observed BID vs. QD (controlled for dose) supports the contribution of sustained higher levels of CDK7 inhibition between doses to antitumor activity, and informs the evaluation of intermittent dosing in patients to optimize single agent or combination SY-5609 dose and schedule selection. SY-5609 results of intermittent dosing regimens in patients with advanced solid tumors are reported separately (Sharma, ESMO 2021).
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Syros Pharmaceuticals.
Funding
Syros Pharmaceuticals.
Disclosure
L. Johannessen, W. Dworakowski, P. Sawant, A. Lefkovith, A. D'Ippolito, M. Eaton, S.H. Henry, G. Hodgson: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals. N. Ke: Financial Interests, Personal and Institutional, Full or part-time Employment: Syros Pharmaceuticals.