Background: LY3143921 hydrate is an orally administered ATP-competitive inhibitor of CDC7, a serine/threonine kinase regulatory protein overexpressed in many cancer types. Following successful preclinical studies, a first-in-human phase I trial of LY3143921 hydrate was initiated in patients with advanced solid tumors. We report the pharmacokinetics of LY3143921 hydrate in this ongoing Cancer Research UK study.

Methods: Eligible patients were those with histologically proven advanced/metastatic solid tumors for which no further standard therapy options were available. Patients were administered LY3143921 hydrate as a single oral dose on Day -7, followed by daily administration (dose levels 30-270mg) or twice daily administration (dose levels 150 and 180mg) on study days 1-21. Drug administration was carried out with patients in either a fasted or fed state as shown in Table 1. Samples for pharmacokinetic analysis were obtained following a single drug dose on Day -7 at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours. Additional samples were taken on Day 1 of treatment at doses of 150 and 180mg to investigate potential differences in pharmacokinetics in fed versus fasted states (Day -7 fed versus Day 1 fasted). Samples were analysed using a validated LC-MS/MS assay with a LLOQ of 0.1 ng/mL. Pharmacokinetic analysis was carried out using Certara WinNonlin software (version 6.3) to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent volume of distribution (Vz/F) and apparent clearance (CL/F) of LY3143921 hydrate. Assessment of dose proportionality was made by assessment of graphical plots of AUC versus dose level.

Table 1:

Summary of LY3143921 hydrate pharmacokinetic data on Day -7 (single dose data)

Dose level (mg)Number of patientsFed / fastedCmax (ng/mL)AUC0-24h (ng/mL.h)Half-life (h)CL/F (L/h)Vz/F (L)
30 Fasted 184.4 425 3.35 70.1 339 
60 Fasted 175.0 502 2.42 119.4 418 
120 Fasted 1130 3138 2.17 38.2 120 
180 10 Fasted 144 - 814 2505 ± 990 4.2 ± 4.0 79.5 ± 23.9 475 ± 473 
270 Fasted 474 - 1512 6374 ± 1475 3.4 ± 1.8 43.8 ± 8.9 226 ± 158 
150 Fed 334 - 632 1997 ± 496 4.4 ± 1.9 77.2 ± 16.4 514 ± 288 
180 Fed 492 - 1600 2994 ± 979 3.2 ± 0.8 64.2 ± 19.4 290 ± 112 
Dose level (mg)Number of patientsFed / fastedCmax (ng/mL)AUC0-24h (ng/mL.h)Half-life (h)CL/F (L/h)Vz/F (L)
30 Fasted 184.4 425 3.35 70.1 339 
60 Fasted 175.0 502 2.42 119.4 418 
120 Fasted 1130 3138 2.17 38.2 120 
180 10 Fasted 144 - 814 2505 ± 990 4.2 ± 4.0 79.5 ± 23.9 475 ± 473 
270 Fasted 474 - 1512 6374 ± 1475 3.4 ± 1.8 43.8 ± 8.9 226 ± 158 
150 Fed 334 - 632 1997 ± 496 4.4 ± 1.9 77.2 ± 16.4 514 ± 288 
180 Fed 492 - 1600 2994 ± 979 3.2 ± 0.8 64.2 ± 19.4 290 ± 112 

Results: Table 1 provides a summary of the pharmacokinetic parameters obtained on Day -7 following a single dose of LY3143921 hydrate (data expressed as range or mean ± SD as appropriate). Overall dose-dependent increases in exposure (based on Cmax and AUC) were observed. There was a general trend towards higher Cmax and AUC values following administration in a fasted versus fed state following a dose of 180 mg, but this was inconsistent across the limited number of patients for who these data were available on both Day -7 (fed) and Day 1 (fasted).

Conclusion: The pharmacokinetic data generated to date are consistent with dose dependent increases in drug exposure observed with a flat dosing regimen for LY3143921 hydrate.

Citation Format: Shelby Barnett, Melanie Griffin, Richard H. Wilson, Elizabeth R. Plummer, Jeffry T. Evans, Victoria Coyle, Sally Clive, Lisa Godfrey, Nicola Dobbs, Lesley McGuigan, Sue Brook, Gavin Halbert, Gareth J. Veal. Pharmacokinetics of the CDC7 inhibitor LY3143921 hydrate, a CRUK first-in-human phase I trial in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3014.