Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors

Abstract

Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40-102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).

Keywords: 2-hydroxyglutarate; Isocitrate dehydrogenase 1 inhibitor; Ivosidenib; Pharmacodynamics; Pharmacokinetics.

Conflict of interest statement

B. Fan, S.S. Pandya, E. Manyak, L. Jiang, G. Liu, T. Nimkar, C. Gliser, M. Prahl Judge, and H. Yang are employees and stockholders of Agios. S. Agresta and D. Dai were employees and stockholders of Agios at the time of the study. E. Manyak was an employee of Agios at the time of the study and current stockholder of Agios. I.K. Mellinghoff has received research funding from General Electric, Amgen, and Lilly; has advisory roles with Agios, Puma Biotechnology, and Debiopharm Group; and has received an honorarium from Roche for a presentation. P.Y. Wen has participated in advisory boards for Abbvie, Agios, AstraZeneca, Blue Earth Diagnostics, Eli Lilly, Genentech/Roche, Immunomic Therapeutics, Kadmon, Kiyatec, Puma, Vascular Biogenics, Taiho, Deciphera, and VBI Vaccines; has acted as speaker for Merck and Prime Oncology; has received research support from Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, and VBI Vaccines. M.A. Lowery is a consultant and advisory board member for Agios and an advisory board member for Celgene, EMD Serono, and Roche. L. Goyal is an advisory board member for Pieris Pharmaceuticals and Debiopharm. W.D. Tap has received clinical trial funding from Agios during the conduct of the study; personal fees from Eli Lilly, EMD Serono, Novartis, Eisai, Janssen, Immune Design, Adaptimmune, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, Agios, and Plexxikon; holds a patent for Companion Diagnostic for CDK4 inhibitors - 14/854,329 pending to MSKCC/SKI; a patent for Methods of Treating Metastatic Sarcoma Using Talimogene Laherparepvec (T-Vec) and Pembrolizumab Combination Therapy - 62/671,625 pending to MSKCC/SKI; is a scientific advisory board member and stock owner for Certis Oncology Solutions and Atropos Therapeutics.

Figures

Fig. 1

Representative graph of dose proportionality assessment for AUC0-72h (a) and Cmax (b) after single doses of ivosidenib (day −3) in patients with cholangiocarcinoma, chondrosarcoma, and other solid tumors (power model with 95% CI). Point-wise 95% CIs are shown. Ln-transformed PK parameters were back-transformed to the original scale by exponentiation

Fig. 2

Plasma ivosidenib CLss/F after multiple oral doses of ivosidenib 500 mg QD (cycle 2, day 1, dose escalation and expansion) by renal function category (based on baseline eGFR) (a), hepatic function category (b), concomitant CYP3A4 inhibitors (c), and concomitant CYP3A4 inducers (d). Glioma includes non-enhancing and enhancing glioma. Non-glioma includes cholangiocarcinoma, chondrosarcoma, and other solid tumors. Horizontal lines denote median; boxes denote 25th to 75th percentiles; whiskers were plotted using the Tukey method

Fig. 3

Summary of average plasma 2-HG concentrations over time by dose category and tumor type (dose escalation and expansion combined) for cholangiocarcinoma (a) and chondrosarcoma (b). The dotted horizontal lines denote average 2-HG levels observed in healthy volunteers. Abbreviations: C1D15, cycle 1 day 15; C2D1, cycle 2 day 1.

Fig. 4

Longitudinal plots of plasma ivosidenib concentration (a) and percent 2-HG inhibition (b) after oral administration of ivosidenib 500 mg QD in patients with cholangiocarcinoma (dose escalation and expansion combined). The dotted horizontal line in panel a denotes the predicted efficacious level of ivosidenib

Fig. 5

Exposure-response analyses. Ivosidenib exposure (AUCss) distribution versus occurrence of grade ≥ 3 adverse events for patients with cholangiocarcinoma, chondrosarcoma and other solid tumors (a), and glioma (non-enhancing and enhancing) (b). Panel c shows exposure (AUCss) distribution versus clinical best response in patients with cholangiocarcinoma, chondrosarcoma and other solid tumors. Abbreviations: AE, adverse event; PD, progressive disease; PR, partial response; SD, stable disease