Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase
Fontana, E. Lee, E Rosen, E Spigel, D Hojgaard, M Lheureux, S Mettu, N B Carter, Louise Plummer, R Manley, P
Fontana, E.
Lee, E
Rosen, E
Spigel, D
Hojgaard, M
Lheureux, S
Mettu, N B
Carter, Louise
Plummer, R
Manley, P
Citations
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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."
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Fontana, E, Lee, E, Rosen, E, Spigel, D, Hojgaard, M, Lheureux, S, Mettu, N B, Carter, Louise, et al Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Annals of Oncology . 2022