Evaluation of food effect on pharmacokinetics (PK) of GDC-0449 (G) in advanced solid tumor patients.

Abstract

e13106 Background: GDC-0449 (Vismodegib, Genentech), an orally bioavailable small-molecule SMO (Smoothened) inhibitor, was recently approved for advanced basal cell carcinoma (BCC) and is being evaluated in other solid tumors. This study sought to determine whether there is a significant effect of food on the PK of G. Methods: In part I, patients (pts) were randomized 1:1 to fasting overnight (FO) or a high fat meal (HF) before a single dose of G 150 mg. The study was later amended to 1:1:2 randomization to FO, HF or a low fat meal (LF). Plasma concentrations of G were determined by a validated liquid chromatography-tandem mass spectrometry assay. PK endpoints were observed Cmax, observed Tmax, and AUC (0-24 and 0-168 hours). In part II, pts randomized to FO or HF in part I took G 150 mg/day in a fasting state, while pts randomized to LF took G 150 mg/day in a fed state. PK endpoints after two weeks were steady state (ss) Cmax, ss Tmax, and ss AUC (0-24 hours). 60 pts enrolled 10/09-11/11, of which 43 were evaluable for PK: 18 FO; 14 HF; 11 LF. Pt characteristics: Female 53%; median age 59; PS 0: 62%, 1: 38%. Tumor types: 43% colorectal; 17% pancreatic; 40% other. Results: PK data were log-transformed for analysis. AUC (0-168 hours) after a single dose was higher in HF than in FO pts (p = 0.049); ratio of geometric means = 1.46 (90% CI = 1.07-1.99). There was a trend toward higher Cmax after a single dose in HF than in FO pts (p = 0.071); ratio of geometric means = 1.39 (90% CI = 1.03-1.88). There were no significant differences between groups for single dose AUC (0-24 hours) and Tmax. There were no significant differences between fasting and fed groups for ss Cmax, ss Tmax, or ss AUC (0-24 hours). The frequencies of drug-related Grade ≥ 3 toxicities were similar in the fasting and fed groups. There were no objective responses; 11 pts (18%) had stable disease for a median duration of 16 weeks and a maximum of 104 weeks (BCC). Conclusions: A high fat meal increases plasma exposure to a single dose of G, but there are no significant PK or safety differences between fasting and fed groups at ss. GDC-0449 can be taken with or without food for daily dosing. This study design is an efficient way to evaluate the effect of food on oral anti-cancer drugs. Supported by NCI grant 5U01-CA69852-12.