ZINCLO-HAND: Zinc and Clobetasol for the Prevention of Regorafenib-Induced Hand-Foot Skin Reaction

Background and Rationale Hand-foot skin reaction (HFSR) is a common dose-limiting toxicity associated with regorafenib treatment, occurring in more than 50% of patients and leading to treatment modifications in up to 15% of cases. Despite its clinical significance, no standardized prophylactic strategy exists.

High-potency topical corticosteroids, such as clobetasol propionate 0.05%, have demonstrated efficacy in reducing HFSR severity, particularly when used preemptively. Additionally, recent studies suggest that oral zinc supplementation may contribute to maintaining skin integrity and reducing inflammatory responses, thereby mitigating HFSR severity. However, the comparative efficacy of these interventions and their potential synergistic effect have not been well established.

Study Objectives This study aims to evaluate whether oral zinc supplementation and/or transdermal clobetasol cream effectively prevent and reduce the severity of regorafenib-induced HFSR, thereby improving treatment adherence and patient quality of life.

Study Design

This is a prospective, non-randomized, interventional study involving approximately 120 patients receiving regorafenib at multiple oncology centers in Türkiye. Participants will be assigned to one of three intervention arms based on their treating physician's discretion:

Oral zinc supplementation + transdermal clobetasol cream Transdermal clobetasol cream alone Oral zinc supplementation alone Interventions Oral Zinc Supplementation: 78 mg zinc gluconate, administered twice daily for 8 weeks.

Transdermal Clobetasol Cream: Clobetasol propionate 0.05%, applied twice daily to the palms and soles for 8 weeks.

Assessment & Follow-up HFSR severity and incidence will be evaluated using CTCAE v5.0 criteria. Patient-reported outcomes will be assessed via Hand-Foot Syndrome Scale-14 (HFS-14) and FACT-G quality of life questionnaire.

Regorafenib adherence (dose modifications, treatment discontinuations) will be monitored.

Survival analysis (PFS and OS) will be conducted at 6 months. By comparing these prophylactic strategies, this study seeks to identify the most effective approach to minimize HFSR burden in patients undergoing regorafenib therapy, potentially influencing future clinical practice.

Inclusion criteria

• Age ≥18 years
• Histologically confirmed solid tumor for which regorafenib is an approved treatment (e.g., metastatic colorectal cancer, gastrointestinal stromal tumor, hepatocellular carcinoma, glioblastoma, or others)
• Initiating regorafenib treatment for the first time
• ECOG performance status of 0-2
• Baseline hand-foot skin reaction (HFSR) of Grade 0 (no prior HFSR symptoms) according to CTCAE v5.0
• Adequate organ function, including:

AST/ALT ≤ 3× upper limit of normal (ULN) Creatinine clearance > 50 mL/min Hemoglobin ≥ 9 g/dL Platelet count ≥ 75,000/mm³

• Able to tolerate oral zinc supplementation and/or topical corticosteroids
• Willing to participate and provide informed consent

Exclusion criteria

• Pre-existing dermatologic conditions affecting the hands or feet (e.g., psoriasis, eczema, active infections)
• Prior Grade ≥1 HFSR from any VEGFR-TKI therapy
• Allergy or known hypersensitivity to zinc, clobetasol, or other study components