Pharmacokinetic (PK) profile and food effect of RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase in patients (pts) with cancer

Abstract

"Background: RP-3500 is an oral ATR inhibitor (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. The dose-escalation portion of the TRESR study (NCT04497116) evaluated RP-3500 5e200 mg once daily (QD) or twice daily at defined intermittent schedules in 120 pts. Methods: RP-3500 plasma levels were assessed and PK parameters were determined by non-compartmental analysis (Phoenix WinNonLin) in pts with evaluable plasma concentration-time points. To determine the effect of food on RP-3500 PK, 12 pts received a single dose of RP-3500 following a standard high-fat meal on Day -3 and after a 24-hr fast on Day 1. Serial blood samples were collected for PK analysis at baseline and after RP-3500 administration. Results: 120 pts had sufficient data on day 1, cycle 1, to report PK parameters. Overall, 323 plasma concentration-time profiles were collected. Plasma exposure was dose-linear with low within-pt variability and a T½ of w6 hr. No accumulation of RP-3500 was observed after multiple doses were given. At therapeutic doses of 120 mg and 160 mg QD on day 1, cycle 1, mean AUC0-24 was 33.6 and 48.2 mg٠hr/mL, respectively, and mean Cmax was 5.74 and 7.64 mg/mL, respectively. Within the therapeutic dose range, median Tmax was 2 hr (range 0.5e6). When administered with a high fat meal, RP-3500 median Tmax was delayed by 3 hrs and mean Cmax was reduced by 45% compared with fasting values within this cohort. Mean AUC0-24 was 16% lower compared with AUC0-24 in the fasted state. Importantly, the plasma levels required for the pharmacological activity of RP-3500 did not substantially differ between the fed and fasted states. Conclusions: The PK profile of RP-3500 is predictable with low observed variability. RP-3500 given orally to pts at recommended doses of 120-160 mg QD on 3 days/ week, with or without food, reaches or exceeds preclinically defined target exposure requirements (Roulston et al., Mol Cancer Ther. 2021). RP-3500 can be administered with or without food without affecting PK parameters relevant to tolerability and therapeutic window."