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

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    Authors
    Fontana, E.
    Lee, E
    Rosen, E
    Spigel, D
    Hojgaard, M
    Lheureux, S
    Mettu, N B
    Carter, Louise
    Plummer, R
    Manley, P
    Ulanet, D
    Rimkunas, V
    Silverman, I M
    O'Connell, J
    McDougall, R
    Wainszelbaum, M
    Xu, Y
    Koehler, M
    Fretland, A J
    Yap, T A
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    Affiliation
    Sarah Cannon Research Institute, Nashville, TN, USA
    Issue Date
    2022
    
    Metadata
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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."
    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
    URI
    http://hdl.handle.net/10541/625206
    DOI
    10.1016/j.annonc.2022.01.068
    Additional Links
    https://dx.doi.org/10.1016/j.annonc.2022.01.068
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.annonc.2022.01.068
    Scopus Count
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