Data from Phase I Trial of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Refractory, Locally Advanced or Metastatic Solid Tumors

Abstract

<div>Abstract<p><b>Purpose:</b> The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed.</p><p><b>Experimental Design:</b> Sixty-eight patients received GDC-0449 at 150 mg/d (<i>n</i> = 41), 270 mg/d (<i>n</i> = 23), or 540 mg/d (<i>n</i> = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of <i>GLI1</i> expression in noninvolved skin were assessed.</p><p><b>Results:</b> Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of <i>GLI1</i> down-modulation was observed in noninvolved skin.</p><p><b>Conclusions:</b> GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted. <i>Clin Cancer Res; 17(8); 2502–11. ©2011 AACR</i>.</p></div>