Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease

Abstract

Hedgehog signaling plays a key role in tissue fibrosis, the pathological hallmark of chronic graft-versus-host disease (cGVHD). We conducted a phase 1 trial of sonidegib, a selective antagonist of the hedgehog coreceptor Smoothened, for the treatment of steroid-refractory cGVHD. After a 3+3 study design, sonidegib was administered for up to 12 cycles of 28 days each, using 3 doses: 200 mg/day (dose level 1), 400 mg/day (dose level 2), and 600 mg/day (dose level 3). Seventeen patients were enrolled. The median number of cycles completed was 6 (range, 0-12). There was only 1 dose-limiting toxicity (cohort 2, grade 3 creatine phosphokinase increase) observed. Immunohistochemical evaluation of skin biopsies revealed decreased protein expression of hedgehog signaling pathway molecules with sonidegib therapy. Clinically, 8 patients (47%) had a partial response in skin or sclerodermatous disease, 6 patients had no response, and 3 were not evaluable. Clinical responses were assessed by treating physicians and not by National Institutes of Health criteria. Overall, patients reported worsening of quality of life, which was more severe in clinical nonresponders. Accrual was terminated early as a result of the cumulative toxicity burden not attributed to sonidegib and patient decisions to stop taking sonidegib. We believe hedgehog signaling inhibition warrants further investigation in patients with cGVHD because of the association with clinical responses and immunohistochemical changes. This trial was registered at www.clinicaltrials.gov as #NCT02086513.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Immunohistochemical evaluation of hedgehog signaling pathway molecules. (A) Mean H-scores for hedgehog signaling pathway molecules obtained from pre- and posttreatment skin biopsies from 13 evaluable patients. The H-score is calculated by multiplying the percentage of cells staining for a given molecule in a fixed field by the staining intensity (0 = none, 1 = weak, 2 = moderate, 3 = intense), with final scores ranging from 0 to 300. (B) Histochemical staining demonstrating a decrease in staining intensity for hedgehog pathway molecules in skin biopsies from a sample clinical responder. Hematoxylin and eosin (H&E) stain, original magnification ×600; all other stains, original magnification ×200. GSK3β, glycogen synthase kinase 3 β; Ihh, Indian hedgehog; Shh, sonic hedgehog.