Abstract
This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.
Highlights
Aberrant hedgehog pathway activation has been implicated in a number of cancers [1,2,3,4,5,6,7,8,9]
After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose
Mean total and unbound vismodegib steady-state concentrations were lower after times per week (TIW) and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug
Summary
Aberrant hedgehog pathway activation has been implicated in a number of cancers [1,2,3,4,5,6,7,8,9]. Vismodegib (GDC-0449; 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]4-[methylsulfonyl]benzamide) is a potent small molecule inhibitor of the hedgehog signaling pathway and is being developed for treatment of various cancers [10,11,12,13]. Medulloblastoma [14], colon, and pancreatic tumors [9]. Data from these studies were used to established a target plasma concentration of vismodegib to meet, or exceed, the unbound IC95 for Gli inhibition In a phase I study for patients with advanced malignancies, vismodegib was well tolerated, with pharmacodynamic (PD) evidence of hedgehog pathway inhibition via GLI1 suppression, and tumor regressions in patients with basal cell carcinoma and medulloblastoma [10, 11, 13]
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