Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors

Abstract

Purpose: 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.

Experimental design: Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed.

Results: 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 GLI1 down-modulation was observed in noninvolved skin.

Conclusions: 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.

Figure 1

Abnormalities in hedgehog pathway signaling, mechanism of GDC-0449 activity, and study schema. A, mechanisms of abnormal hedgehog signaling associated with different cancers are shown in the first 3 panels. Type I, left, BCC and medulloblastoma are associated with mutations in hedgehog signaling pathways; mutations in PTCH1 (pink star) can prevent PTCH1 from inhibiting SMO activity, or mutations in SMO (yellow star) can constitutively activate SMO, resulting in downstream effects of increased GL1 expression. Type III, middle, production of hedgehog ligand by tumor cells may stimulate stromal cells to produce factors associated with tumor growth, possibly including vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF). The right panel shows how GDC-0449 inhibits hedgehog pathway signaling by inhibiting the activity of SMO. B, a schema for the phase I study.

Figure 2

Pharmacokinetics and Pharmacodynamics of GDC-0449. A, steady-state concentrations [C_ss, mean, and SD] are shown for total and unbound GDC-0449, by dose cohorts. B, Pharmacokinetic plasma concentrations of total GDC-0449 (mmol/L), color-coded by dose cohort, are shown for individual patients over 13 weeks. C, Plots of average GDC-0449 steady state concentrations in the different cohorts. BCC-150 and BCC-270 refer to the cohort of patients with BCC. PII-150 refers to the new GDC-0449 formulation that is being used in phase II studies. The line in the middle of the box represents the median, the top and bottom box limits represent the 25th and 75th percentiles, and the top and bottom bars represent 1.5 times the interquartile range. D and E, Skin punch biopsies or hair follicles were processed for analysis of GLI1 mRNA expression as described in the Methods section. Levels of GLI1 down-modulation, compared with pretreatment patient specimens, are shown for individual patients grouped by dose and staging cohorts.

Figure 2

Pharmacokinetics and Pharmacodynamics of GDC-0449. A, steady-state concentrations [C_ss, mean, and SD] are shown for total and unbound GDC-0449, by dose cohorts. B, Pharmacokinetic plasma concentrations of total GDC-0449 (mmol/L), color-coded by dose cohort, are shown for individual patients over 13 weeks. C, Plots of average GDC-0449 steady state concentrations in the different cohorts. BCC-150 and BCC-270 refer to the cohort of patients with BCC. PII-150 refers to the new GDC-0449 formulation that is being used in phase II studies. The line in the middle of the box represents the median, the top and bottom box limits represent the 25th and 75th percentiles, and the top and bottom bars represent 1.5 times the interquartile range. D and E, Skin punch biopsies or hair follicles were processed for analysis of GLI1 mRNA expression as described in the Methods section. Levels of GLI1 down-modulation, compared with pretreatment patient specimens, are shown for individual patients grouped by dose and staging cohorts.