Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

Abstract

"Background: Dose-finding studies typically establish a maximum tolerated dose, a recent shift from this “more is better” approach towards long-term tolerability is of interest. The ongoing RP-3500 TRESR study (NCT04497116) used a comprehensive, non-randomized, dose-finding approach, focusing on longer-term tolerability to establish a patient (pt)-specific therapeutic dose level. Methods: Bayesian Optimal Interval-based dose escalation was informed by pre clinical in vivo pharmacokinetic (PK)/pharmacodynamic (PD) models (LoVo/Granta 519), clinical PK, PD biomarkers (g-H2AX), circulating tumor DNA (ctDNA) and safety data. The optimal recommended phase 2 dose (RP2D) schedule (3 days (d) on/4d off) and efficacious dose level (>100mg) for target inhibition were chosen based on pre-clinical and clinical PK and safety data. Decrease in ctDNA mean variant allele frequency (mVAF) was a surrogate of RP-3500 activity. PK/PD modelling contributed to RP2D selection. Hematology data within Cycle 1 were used to develop a nomogram to mitigate anemia, an on-target toxicity. Results: Pts (N¼120) with recurrent tumors with selected ATR-inhibitoresensitizing DNA damage response alterations were enrolled in the dose-escalation portion of TRESR. A subset of pts in three dose-expansion cohorts (N¼25/34/26) below the highest evaluated, non-tolerated dose (200mg, 3d on/4d off) was assessed for long term safety (Table). Conclusions: This dose optimization approach using large pt cohorts at three dosing regimens provides robust evidence to support RP-3500 RP2D in the ongoing studies (160mg, 3d on/4d off, continuous). Consistency of ctDNA mVAF decrease across co horts supports the selected RP-3500 dose level. The hematological toxicity nomogram currently in early clinical testing will guide individualized treatment modifications to further reduce anemia rates while maintaining the therapeutic range of 120-160 mg of RP-3500."