First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

Abstract

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).

Patients and methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.

Results: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.

Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

Figure 1. Pharmacokinetic profile of pictilisib

(A) Plasma concentration versus time profile for all dose levels. (B) Maximum plasma concentration (Cmax) versus dose (C) area under the curve (AUC) versus dose. Solid and dashed lines represent the fitted regression lines for days 1 and 15, respectively

Figure 2

(A) Percentage change in levels of phosphorylated AKT (pAKT) in platelet-rich plasma (PRP) and plasma level of pictilisib up to 24 hours following administration of pictilisib (at RP2D of 330mg) on days 1 and 15 of cycle 1 (n=8). (B) Pictilisib concentration-dependent inhibition of phosphorylated AKT (pAKT) in platelet-rich plasma (PRP) following systemic exposure to pictilisib. Data represent available concentration-matched PRP pAKT inhibition from duration of Phase I investigation

Figure 3. Pharmacodynamic analysis in tumor biopsies

(A) Phospho-S6 (pS6) and phospho-AKT (pAKT) levels in baseline and on-treatment paired tumor biopsies grouped according to AUC0-24 (hr*uM) on day 15. pS6 staining levels were measured using a standard H-Score method, and pAKT staining levels were measured using a validated, qualitative scoring method (represented on y axis). Pre- and on-treatment samples from the same patient were stained in the same experiment and examined blind. Arrows indicate patient 50036. (B) Immunohistochemistry images of pS6 and pAKT from patient 50036. (C) Percent change from baseline of pS6 and pAKT levels. Tumor biopsies for three patients were not evaluable for phospho-AKT and are indicated with an “x”. All patients received doses of >60mg of pictilisib with the exception of patient 50008 who received 45 mg.