A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors

Abstract

3516 Background: Aberrant Hh signaling pathway activation has been implicated in a variety of cancers via both Hh ligand-independent and ligand-dependent overexpression. GDC-0449 is a first-in-human, first-in-class, potent systemic inhibitor of Hh signal transduction. Methods: Refractory solid tumor pts were enrolled in a 3+3 ph I study to evaluate safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD). GDC-0449 was administered orally as a single dose on Day 1 with a 1-week PK break, and then once daily continuously (cycle 1=35 days). Surrogate tissues were assessed for the expression of Hh downstream target gene, Gli1. Results: 19 pts were treated: 150 mg/day (n=7), 270 mg/day (n=9), and 540 mg/day (n=3); median pt age 63 yrs (range 39–84) with ECOG performance status 0–2. There have been no dose-limiting toxicities. Reversible drug-related Gr 3 hyponatremia and fatigue (1 each) were reported. One partial response (150 mg) in basal cell carcinoma (BCC) and 2 stable disease (270 mg) in BCC and adenocystic carcinoma were seen. Unexpectedly high plasma drug concentrations at the 150 and 270 mg dose levels led to the expansion of those cohorts. GDC-0449 PK properties showed a prolonged terminal half-life and drug accumulation, which resulted in surprisingly similar mean steady state plasma concentrations (30–35 μM) across dose levels. Gli1 was down modulated >2-fold in skin biopsies from 11 of 14 pts analyzed. Conclusions: The Hh antagonist GDC-0449 was evaluated at 3 dose levels and demonstrated a unique PK profile. Continuous oral dosing at 150 mg/day demonstrated safety, effective PK concentrations, PD activity, an objective response and clinical benefit, and was selected for ph II studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology