Pharmacokinetics/Dynamics (Pk/Pd) Evaluation And Individual Patient Cross-Over Studies With Growth Trajectory Assessment To Adaptively Develop Ilorasertib.

2563Background: We evaluated PK/PD of the AURK B/VEGFR2 inhibitor ilorasertib. To detect activity in CDKN2A-deficient tumors, we measured changes-in-tumor-burden by CT-volume before, during, and after discontinuation of therapy. Methods: Study 1: open-label, dose-escalation, phase 1 in 58 patients (pts) with advanced solid tumors. Arms I, II, and III assigned: 23 pts (10–180 mg oral QD), 28 pts (40–340 mg oral BID), and 7 pts (8–32 mg i.v. QD), to ilorasertib monotherapy Days 1, 8, and 15 every 28 days. We evaluated PK/PD for validated biomarkers: change-in-diastolic blood pressure (ΔDBP), change-in-plasma [PlGF] (ΔPlGF), and change-in phosphorylated histone H3 (Δ%pHH3) in skin biopsies. Study 2: open-label trial, of 10 solid tumor pts with CLIA-lab-detected CDKN2A disruption. Pts received ilorasertib 250 mg oral BID on same schedule. On CT images collected prior to screening, and ~ study days -7, 49, and 98 individual lesion volumes were determined by central lab semi-automated segmentation algorithms on...