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e-Poster Display session

9P - Preliminary population pharmacokinetic (popPK) co-variates and exposure response (ER) assessment of QT for RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase

Date

07 Mar 2022

Session

e-Poster Display session

Presenters

Elizabeth Lee

Citation

Annals of Oncology (2022) 33 (suppl_1): S3-S6. 10.1016/annonc/annonc842

Authors

E. Lee1, T.A. Yap2, E. Fontana3, E. Rosen4, D. Spigel5, S. Lheureux6, N.B. Mettu7, L. Carter8, R. Plummer9, S. Patel6, R. McDougall6, R. Papp6, S. May6, P. Nejad6, D. Ulanet6, M. Wainszelbaum6, P. Manley10, M. Koehler6, A.J. Fretland6, M. Højgaard11

Author affiliations

  • 1 Dana-Farber Cancer Institute, Boston/US
  • 2 The University of Texas M. D. Anderson Cancer Center, Houston/US
  • 3 Sarah Cannon Research Institute UK, London/GB
  • 4 Memorial Sloan Kettering Cancer Center, New York/US
  • 5 Thoracic Medical Oncology, Nashville/US
  • 6 Repare Therapeutics, Cambridge/US
  • 7 Medical Oncology, Durham/US
  • 8 Institution The Christie NHS Foundation Trust, Manchester/GB
  • 9 Northern Centre for Cancer Care, Newcastle-upon-Tyne/GB
  • 10 Repare Therapeutics, 02142 - Cambridge/US
  • 11 Department of Oncology, Copenhagen/DK
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Abstract 9P

Background

RP-3500 is an oral inhibitor of ATR (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. We report popPK co-variates and effect on QT prolongation in 120 pts treated with RP-3500 in the phase 1 TRESR study (NCT04497116).

Methods

PK samples were collected from 120 pts on multiple days across doses and schedules during the dose-finding portion of the study. Pt demographics and baseline characteristics were collected at study enrollment. Triplicate electrocardiograms (ECGs) were collected prior to any drug administration and in conjunction with PK sampling at time points up to 4 hr post-RP-3500 dose. A popPK model was developed using Phoenix WinNonLin. PK co-variates were analyzed to assess the effect of age, sex, body weight (BW), body surface area (BSA), and renal/hepatic function on RP-3500 PK. Changes in ECG parameters were evaluated in an ER assessment.

Results

Plasma PK samples (N=2627) from 120 pts were analyzed; 85 pts were sampled on at least 3 different days. The PK data set encompassed an RP-3500 dose range of 5–200 mg QD and BID across 2 different weekly regimens: 5 days on/2 days off, 3 days on/4 days off. RP-3500 PK was well described using a 2-compartment model with a lag-time incorporated to accurately describe drug absorption. Preliminary co-variate analysis suggested some variation in RP-3500 PK according to BW and BSA. There was no significant impact on PK values in patients with mild renal or hepatic impairment. Among patients with moderate renal impairment, a small reduction in clearance was observed with limited impact on other compartmental PK values. Results of the initial ER assessment showed no RP-3500-related changes in QT intervals.

Conclusions

These popPK results from TRESR confirm a predictable RP-3500 PK profile with low variability. Importantly, the data indicate that RP-3500-induced changes in QT are unlikely, and strongly support further clinical development of RP-3500 with limited ECG evaluation. Further investigation into the potential need for moderate renal impairment-, BW- or BSA-adjusted RP-3500 dosing is ongoing.

Clinical trial identification

NCT04497116.

Editorial acknowledgement

Editorial assistance was provided by Mike Zbreski, PharmD of Onyx Medica, London, UK, supported by Repare Therapeutics Inc.

Legal entity responsible for the study

Repare Therapeutics.

Funding

Repare Therapeutics.

Disclosure

T.A. Yap: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Constellatior; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Forbius; Financial Interests, Institutional, Research Grant: F-Star; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Haihe; Financial Interests, Institutional, Research Grant: ImmuneSensor; Financial Interests, Institutional, Research Grant: Ionis; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: KSQ; Financial Interests, Institutional, Research Grant: Kyowa; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Rubius; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Scholar Rock; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Vivace; Financial Interests, Institutional, Research Grant: Ribon Therapeutics; Financial Interests, Personal, Advisory Role: Repare Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Almac; Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Artios; Financial Interests, Personal, Advisory Role: Athena; Financial Interests, Personal, Advisory Role: Atrin; Financial Interests, Personal, Advisory Role: Axiom; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Calithera; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: Cybrexa; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: F-Star; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: Guidepoint; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: I-Mab; Financial Interests, Personal, Advisory Role: ImmuneSensor; Financial Interests, Personal, Advisory Role: Jansen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Schrodinger; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Varian; Financial Interests, Personal, Advisory Role: Zai Labs; Financial Interests, Personal, Advisory Role: Zielbio. E. Fontana: Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International. D. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics; Financial Interests, Institutional, Research Grant: Agios; Financial Interests, Institutional, Research Grant: Apollomics; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Arrys Therapeutics; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BIND Therapeutics; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: Blueprint Medicine; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Calithera; Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Celldex; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Denovo Biopharma; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Elevation Oncology; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Evelo Biosciences; Financial Interests, Institutional, Research Grant: G1 Therapeutics; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: GRAIL; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: ImClone Systems; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Kronos Bio; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo Oncology; Financial Interests, Institutional, Research Grant: MacroGenics; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Molecular Partner; Financial Interests, Institutional, Research Grant: Molecular Template; Financial Interests, Institutional, Research Grant: Nektar; Financial Interests, Institutional, Research Grant: Neon Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: Oncologie; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PTC Therapeutics; Financial Interests, Institutional, Research Grant: PureTech Health; Financial Interests, Institutional, Research Grant: Razor Genomics; Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: Transgene; Financial Interests, Institutional, Research Grant: UT Southwester; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Curio Science; Financial Interests, Personal, Advisory Role: EMD Sereno; Financial Interests, Personal, Advisory Role: Evidera; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Intellisphere; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Molecular Templates; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Novocure; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Puma Biotechnology; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Sanofi-Aventis. S. Lheureux: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. N.B. Mettu: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Mereo BioPharma; Financial Interests, Institutional, Research Grant: OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amphivena Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Biomed Valley Discoveries; Financial Interests, Institutional, Research Grant: Erytech Pharma; Financial Interests, Institutional, Research Grant: Incyte Corporation; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Revolution Medicines, Inc; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Marc Lustgarten Pancreatic Cancer Foundation; Financial Interests, Institutional, Research Grant: Armo BioSciences/Eli Lilly; Financial Interests, Institutional, Research Grant: NIH; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb. R. Plummer: Financial Interests, Personal, Advisory Board: Astex Therapeutics; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Cybrexa; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Faber; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other, Honoraria as member of IDMC: Beigene; Financial Interests, Personal, Other, Honoraria as member of IDMC: SOTIO. S. Patel, R. Papp, S. May, M. Koehler: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. R. McDougall, P. Nejad, D. Ulanet, M. Wainszelbaum, P. Manley, A.J. Fretland: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. M. Højgaard: Other, Personal, Advisory Board: LingoMedical; Financial Interests, Personal, Stocks/Shares: Bavarian Nordic; Financial Interests, Personal, Stocks/Shares: Pacific Biosciences; Financial Interests, Personal, Stocks/Shares: Illumina Inc; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Incyte Cooperation; Other, Personal, Member of the Board of Directors: Danish Medicines Council. All other authors have declared no conflicts of interest.

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