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

Impact of Zinc Supplementation and Transdermal Clobetasol in the Prophylaxis of Regorafenib-Induced Hand-Foot Skin Reaction: A Prospective Non-Randomized Study

This study aims to evaluate whether a combination of oral zinc supplementation and transdermal clobetasol cream is effective in preventing and reducing the severity of hand-foot skin reaction (HFSR) induced by regorafenib treatment.

HFSR is one of the most common adverse effects of regorafenib, affecting more than 50% of patients, with 10-15% experiencing severe Grade 3 toxicity. Clobetasol, a high-potency corticosteroid, has been shown to significantly reduce the severity of HFSR when used preemptively rather than reactively. Additionally, recent clinical trials indicate that oral zinc supplementation may further reduce the incidence of Grade ≥2 HFSR.

This prospective, non-randomized interventional study will compare three treatment groups:

Oral zinc supplementation + transdermal clobetasol cream Transdermal clobetasol cream alone Oral zinc supplementation alone The study will assess the effectiveness of these treatments using CTCAE grading, the Hand-Foot Syndrome Scale-14, and quality of life measures (FACT-G, fatigue, and anxiety/depression scales). Additionally, the study will evaluate the impact of HFSR on treatment adherence, regorafenib dose modifications, and overall survival.

The study will enroll approximately 120 patients across multiple centers in Türkiye.

Study Overview

• Status: Completed
• Conditions: Hand-Foot Skin Reaction (HFSR)
• Intervention / Treatment: Dietary supplement: Zinc Supplementation; Drug: Clobetasol Propionate 0.05% Cream

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Afyonkarahisar, Turkey (Türkiye), 03030
    • Afyonkarahisar University of Health Sciences Hospital
  • Ankara, Turkey (Türkiye), 06230
    • Ankara University Faculty of Medicine Hospital
  • Ankara, Turkey (Türkiye), 06230
    • Hacettepe University Faculty of Medicine Hospital
  • Diyarbakır, Turkey (Türkiye), 21280
    • Dicle University Hospital
  • Tekirdağ, Turkey (Türkiye), 59100
    • Tekirdağ Namık Kemal University Hospital
  • Van, Turkey (Türkiye), 65080
    • Van Yüzüncü Yıl University Dursun Odabaş Hospital
  • Meram
    • Konya, Meram, Turkey (Türkiye), 42080
      • Necmettin Erbakan University Meram Faculty of Medicine Hospital
  • Nilüfer
    • Bursa, Nilüfer, Turkey (Türkiye), 16059
      • Bursa Uludag University Hospital
  • Ortahisar
    • Trabzon, Ortahisar, Turkey (Türkiye), 61080
      • Karadeniz Technical University Hospital
  • Serdivan
    • Sakarya, Serdivan, Turkey (Türkiye), 54050
      • Sakarya University Hospital
  • Yenimahalle
    • Ankara, Yenimahalle, Turkey (Türkiye), 06170
      • Ankara Etlik City Hospital
    • Ankara, Yenimahalle, Turkey (Türkiye), 06200
      • Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital
    • Ankara, Yenimahalle, Turkey (Türkiye), 06500
      • Gazi University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zinc + Clobetasol Group; Participants in this group will receive oral zinc supplementation (78 mg zinc gluconate twice daily) combined with topical clobetasol propionate 0.05% cream, applied twice daily to the palms and soles for 8 weeks. This group aims to evaluate the combined efficacy of zinc and clobetasol in preventing regorafenib-induced hand-foot skin reaction (HFSR).	Dietary supplement: Zinc Supplementation; Participants assigned to zinc-containing arms will receive oral zinc gluconate supplementation (78 mg twice daily) for 8 weeks. This intervention aims to evaluate the effect of zinc in preventing and reducing the severity of regorafenib-induced hand-foot skin reaction (HFSR).; Drug: Clobetasol Propionate 0.05% Cream; Participants assigned to clobetasol-containing arms will receive topical clobetasol propionate 0.05% cream, applied twice daily to the palms and soles for 8 weeks. This intervention aims to assess the efficacy of clobetasol in preventing regorafenib-induced HFSR.
Experimental: Clobetasol Alone Group; Participants in this group will receive topical clobetasol propionate 0.05% cream, applied twice daily to the palms and soles for 8 weeks. This group aims to assess the efficacy of clobetasol alone in preventing regorafenib-induced HFSR.	Drug: Clobetasol Propionate 0.05% Cream; Participants assigned to clobetasol-containing arms will receive topical clobetasol propionate 0.05% cream, applied twice daily to the palms and soles for 8 weeks. This intervention aims to assess the efficacy of clobetasol in preventing regorafenib-induced HFSR.
Experimental: Zinc Alone; Participants in this group will receive oral zinc supplementation (78 mg zinc gluconate twice daily) for 8 weeks. This group aims to determine the role of zinc alone in reducing the severity of regorafenib-induced HFSR.	Dietary supplement: Zinc Supplementation; Participants assigned to zinc-containing arms will receive oral zinc gluconate supplementation (78 mg twice daily) for 8 weeks. This intervention aims to evaluate the effect of zinc in preventing and reducing the severity of regorafenib-induced hand-foot skin reaction (HFSR).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity of Hand-Foot Skin Reaction (HFSR) at Week 8	The incidence and severity of hand-foot skin reaction (HFSR) will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The proportion of patients experiencing Grade ≥2 HFSR will be compared between the intervention groups to evaluate the efficacy of zinc supplementation and/or clobetasol in preventing HFSR.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Hand-Foot Skin Reaction (HFSR)	The time from the onset of Grade ≥2 HFSR to its resolution (return to Grade 1 or lower) will be measured in each intervention group. The effectiveness of zinc supplementation and/or clobetasol in shortening HFSR duration will be evaluated.	8 weeks
Regorafenib Dose Modifications Due to HFSR	The percentage of participants requiring dose reduction, dose delay, or treatment discontinuation due to HFSR will be recorded. The impact of prophylactic zinc supplementation and/or clobetasol on maintaining regorafenib treatment adherence will be assessed.	8 weeks
Quality of Life (FACT-G Score Change)	Changes in quality of life (QoL) will be assessed using the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire. QoL scores at baseline and at Week 8 will be compared among the intervention groups. The FACT-G total score ranges from 0 to 108, with higher scores indicating better quality of life.	Baseline and 8 weeks
Progression-Free Survival (PFS) in Patients with and without Severe HFSR	The time from the start of regorafenib treatment to disease progression or death from any cause, whichever occurs first.	Up to 6 months
Overall Survival (OS) in Patients with and without Severe HFSR	The time from the start of regorafenib treatment to death from any cause.	6 months

Collaborators and Investigators

• Sponsor: Gazi University
• Investigators: Study Chair: Ozan Yazıcı, Prof., Gazi University

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2025
• Primary Completion (Actual): September 1, 2025
• Study Completion (Actual): September 7, 2025

Study Registration Dates

• First Submitted: February 21, 2025
• First Submitted That Met QC Criteria: February 26, 2025
• First Posted (Actual): March 4, 2025

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: September 9, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma (HCC); Clobetasol; Gastrointestinal Stromal Tumor (GIST); Metastatic Colorectal Cancer (mCRC); Zinc Supplementation; Regorafenib-Induced Skin Toxicity
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Colonic Diseases; Carcinoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Carcinoma, Hepatocellular; Colorectal Neoplasms; Gastrointestinal Stromal Tumors; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Betamethasone; Clobetasol
• Other Study ID Numbers: AESH-EK-2025-042; Ankara Etlik City Hospital EC (Other Identifier: Republic of Türkiye Ministry of Health, Ankara Etlik City Hospital Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared due to privacy regulations and institutional policies. Data access is restricted to the study team and authorized personnel to ensure compliance with ethical guidelines and patient confidentiality

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No