5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

E. Fontana; E. Lee; E. Rosen; D. Spigel; M. Højgaard; S. Lheureux; N.B. Mettu; L. Carter; R. Plummer; P. Manley; D. Ulanet; V. Rimkunas; I.M. Silverman; J. O'Connell; R. McDougall; M. Wainszelbaum; Y. Xu; M. Koehler; A.J. Fretland; T.A. Yap

doi:10.1016/j.annonc.2022.01.068

5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

E. Fontana, E. Lee, E. Rosen, D. Spigel, M. Højgaard, S. Lheureux, N.B. Mettu, L. Carter, R. Plummer, P. Manley, D. Ulanet, V. Rimkunas, I.M. Silverman, J. O'Connell, R. McDougall, M. Wainszelbaum, Y. Xu, M. Koehler, A.J. Fretland, T.A. Yap

Research output: Contribution to conference › Abstract › peer-review

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

Original language	English
Pages	S3-S4
DOIs	https://doi.org/10.1016/j.annonc.2022.01.068
Publication status	Published - Mar 2022

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10.1016/j.annonc.2022.01.068

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Fontana, E., Lee, E., Rosen, E., Spigel, D., Højgaard, M., Lheureux, S., Mettu, N. B., Carter, L., 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. (2022). 5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. S3-S4. https://doi.org/10.1016/j.annonc.2022.01.068

@conference{eddd56e6473941008d378aeac9f1c580,

title = "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 {\textcopyright} 2022 European Society for Medical Oncology",

author = "E. Fontana and E. Lee and E. Rosen and D. Spigel and M. H{\o}jgaard and S. Lheureux and N.B. Mettu and L. Carter and R. Plummer and P. Manley and D. Ulanet and V. Rimkunas and I.M. Silverman and J. O'Connell and R. McDougall and M. Wainszelbaum and Y. Xu and M. Koehler and A.J. Fretland and T.A. Yap",

year = "2022",

month = mar,

doi = "10.1016/j.annonc.2022.01.068",

language = "English",

pages = "S3--S4",

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Fontana, E, Lee, E, Rosen, E, Spigel, D, Højgaard, M, Lheureux, S, Mettu, NB, Carter, L, Plummer, R, Manley, P, Ulanet, D, Rimkunas, V, Silverman, IM, O'Connell, J, McDougall, R, Wainszelbaum, M, Xu, Y, Koehler, M, Fretland, AJ & Yap, TA 2022, '5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase', pp. S3-S4. https://doi.org/10.1016/j.annonc.2022.01.068

TY - CONF

T1 - 5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

AU - Fontana, E.

AU - Lee, E.

AU - Rosen, E.

AU - Spigel, D.

AU - Højgaard, M.

AU - Lheureux, S.

AU - Mettu, N.B.

AU - Carter, L.

AU - Plummer, R.

AU - Manley, P.

AU - Ulanet, D.

AU - Rimkunas, V.

AU - Silverman, I.M.

AU - O'Connell, J.

AU - McDougall, R.

AU - Wainszelbaum, M.

AU - Xu, Y.

AU - Koehler, M.

AU - Fretland, A.J.

AU - Yap, T.A.

PY - 2022/3

Y1 - 2022/3

N2 - 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

AB - 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

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U2 - 10.1016/j.annonc.2022.01.068

DO - 10.1016/j.annonc.2022.01.068

M3 - Abstract

SP - S3-S4

ER -

5MO 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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