Data from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials

• DOI: 10.1158/1078-0432.c.6879437.v1
• Publication Date: 2023-10-13T07:45:01Z
• Authors: Eduardo Rodríguez...; Catherine J. Lee; Teresa Caballero-...; Carmen Martínez; Clara García-Cald...; María Reyes Jimén...; María Aránzazu Be...; Lucía López-Corral; Ana Triguero; Lynn Onstad; Mitchell E. Horwitz; Stefanie Sarantop...; Stephanie J. Lee; José Antonio Pére...
• Keywords: Tolerability; Smoothened; Refractory (planetary science); Dysgeusia

<div>AbstractPurpose:<p>Sclerotic chronic GVHD (scGVHD) is characterized by progressive skin fibrosis and frequent refractoriness to available therapies. Aberrant activation of Hedgehog signaling in dermal fibroblasts has been implicated scGVHD. Here, we report the results two phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) that evaluated glasdegib, a smoothened antagonist, as novel therapeutic agent refractory scGVHD.</p>Patients Methods:<p>Adult patients with active scGVHD after ≥1 (FHD) or ≥2 (GETH-TC) lines therapy were enrolled. Primary endpoints dose-limiting toxicity (DLT) MTD GETH-TC trial, safety tolerability measures FHD trial. Glasdegib was administered once daily 28-day cycles. Responses scored per 2014 NIH cGVHD criteria. Correlative performed evaluate role fibroblast-independent immune mechanisms on clinical activity.</p>Results:<p>Twenty 15 recruited. Treatment-emergent grade (G) adverse events (AE) trial included muscle cramps (85%), alopecia (50%), dysgeusia (35%). Two experienced DLT (G3 cramps), established at 50 mg. G3 most frequently reported AE (33%) At 12-months, skin/joint overall response rate 65% (all partial responses) 47% (6 responses, 1 complete response) cohort. No correlates identified.</p>Conclusions:<p>Glasdegib demonstrated promising responses scGVHD, but limited cramping.</p></div>