5MO 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. Method(s): Bayesian Optimal Interval-based dose escalation was informed by preclinical in vivo pharmacokinetic (PK)/pharmacodynamic (PD) models (LoVo/Granta-519), clinical PK, PD biomarkers (gamma-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. Result(s): Pts (N=120) with recurrent tumors with selected ATR-inhibitor-sensitizing DNA damage response alterations were enrolled in the dose-escalation portion of TRESR. A subset of pts in three dose-expansion cohorts (N=25/34/26) below the highest evaluated, non-tolerated dose (200mg, 3d on/4d off) was assessed for long term safety (Table). [Formula presented] Conclusion(s): This dose... Copyright © 2022 European Society for Medical Oncology