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Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase
Eduardo Rodríguez-Arbolí1, Catherine J Lee2, Teresa Caballero-Velázquez1
1Department of Hematology, Hospital Universitario Virgen del Rocío, Seville Biomedicine Institute (IBiS/CSIC), University of Seville, Seville, Spain.
Purpose:
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 in scGVHD. Here, we report the results of two phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) that evaluated glasdegib, a smoothened antagonist, as a novel therapeutic agent in refractory scGVHD.
Patients And Methods:
Adult patients with active scGVHD after ≥1 (FHD) or ≥2 (GETH-TC) lines of therapy were enrolled. Primary endpoints were dose-limiting toxicity (DLT) and MTD in the GETH-TC trial, and safety and tolerability measures in the FHD trial. Glasdegib was administered once daily in 28-day cycles. Responses were scored per 2014 NIH cGVHD criteria. Correlative studies were performed to evaluate the role of fibroblast-independent immune mechanisms on clinical activity.
Results:
Twenty (GETH-TC) and 15 (FHD) patients were recruited. Treatment-emergent grade (G) ≥2 adverse events (AE) in the GETH-TC trial included muscle cramps (85%), alopecia (50%), and dysgeusia (35%). Two patients experienced a DLT (G3 muscle cramps), and the MTD was established at 50 mg. G3 muscle cramps were the most frequently reported AE (33%) in the FHD trial. At 12-months, the skin/joint scGVHD overall response rate was 65% (all partial responses) in the GETH-TC trial and 47% (6 partial responses, 1 complete response) in the FHD cohort. No immune correlates of response were identified.
Conclusions:
Glasdegib demonstrated promising responses in patients with refractory scGVHD, but tolerability was limited by muscle cramping.
Insights
Glasdegib showed promising results for refractory sclerotic chronic graft-versus-host disease (scGVHD), but muscle cramping limited its tolerability. Further research is needed for this fibrotic condition.
Area of Science:
- Hematology
- Oncology
- Dermatology
Background:
- Sclerotic chronic graft-versus-host disease (scGVHD) is a debilitating condition characterized by skin fibrosis and often resistant to standard treatments.
- Aberrant Hedgehog signaling in dermal fibroblasts is a key factor contributing to the fibrotic processes in scGVHD.
Purpose of the Study:
- To evaluate glasdegib, a smoothened antagonist, as a novel therapeutic agent for patients with refractory scGVHD.
- To assess the safety, tolerability, and preliminary efficacy of glasdegib in two Phase I/II clinical trials.
Main Methods:
- Two Phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) enrolled adult patients with active scGVHD who had failed prior therapies.
- Glasdegib was administered orally once daily in 28-day cycles. Primary endpoints included dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety assessments. Response was evaluated using 2014 NIH cGVHD criteria.
Main Results:
- Twenty patients in the GETH-TC trial and 15 in the FHD trial were enrolled. Common adverse events included muscle cramps, alopecia, and dysgeusia.
- The maximum tolerated dose (MTD) of glasdegib was established at 50 mg. Muscle cramping was a significant dose-limiting toxicity.
- At 12 months, the overall response rate for skin/joint scGVHD was 65% in the GETH-TC trial and 47% in the FHD trial, with responses primarily being partial.
Conclusions:
- Glasdegib demonstrated promising clinical activity in patients with refractory scGVHD, suggesting potential as a novel therapeutic option.
- Tolerability, particularly due to muscle cramping, remains a significant challenge that may limit its use.
- No specific immune correlates were identified to predict response to glasdegib treatment.
