Background: GDC-0449 is being developed for treatment of advanced basal cell carcinoma and other solid cancers. In a previous phase I trial in healthy volunteers who were administered a single 150-mg oral dose of GDC-0449, the half-life was determined to be 10 to 14 days (Ding et al., JCB, 878:785-790, ‘10). The primary objectives of the study described here were to evaluate the effects of dosing schedule on safety/tolerability and total and unbound GDC-0449 pharmacokinetics (PK) at steady state (SS).

Methods: This study was a two-stage (loading and maintenance), open-label, Phase Ib study designed to evaluate the PK of daily (QD), three times weekly (TIW), or once weekly (QW) dosing of GDC-0449 in patients with advanced solid tumors refractory to treatment or for whom no standard therapy exists. All patients received a daily 150-mg loading dose for 11 days (loading phase), followed by a maintenance phase during which GDC-0449 was administered by randomized assignment at 150-mg QD (n=20 pts), TIW (n=21 pts), or QW (n=22 pts), for up to an additional 42 days. Total and unbound GDC-0449 plasma concentrations were measured frequently through day 15 and then weekly through day 56 using a validated LC-MS/MS assay. A mechanism-based PK model was previously developed and used to prospectively simulate the impact of dosing schedule on GDC-0449 PK.

Results: The most frequently reported adverse events were consistent with those reported in other GDC-0449 monotherapy clinical trials, with similar incidence regardless of dosing schedule. A time-dependent change in protein binding was observed when comparing single dose to SS GDC-0449 fraction unbound (fu). On average, the single dose fu was 0.002 (+ 0.001), increasing to 0.007 (+0.003) at SS: a 3.5-fold increase (range, 1.5-8.4-fold). Compared with QD dosing, average total and unbound GDC-0449 concentrations at SS were lower for TIW and QW dosing; the extent of the decrease from initial levels was markedly greater for unbound. During the maintenance stage, unbound SS GDC-0449 levels decreased by more than 50% in over half of the TIW patients (up to 76% decrease) and in all of the QW patients (up to 89% decrease). The mechanism-based PK model simulations accurately described the key PK results in a prospective manner.

Conclusions: Overall, the results provide important mechanistic insight into the PK of GDC-0449 and validate the mechanism-based PK model. Importantly, results from this study suggest that patients receiving GDC-0449 TIW or QW would be at risk of not achieving unbound plasma concentrations previously associated with efficacy in advanced BCC. In spite of the long single dose half-life of GDC-0449, the 150-mg QD regimen is most appropriate for ongoing and future clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1310. doi:10.1158/1538-7445.AM2011-1310