Combination Therapy of 5-Fluorouracil and CALcipotriol Versus 5-Fluorouracil in the Treatment of Actinic Keratosis (CALM)

Combination Therapy of 5-Fluorouracil and CALcipotriol Versus 5-Fluorouracil in the Treatment of Actinic Keratosis: a Multicentre Randomized Controlled Clinical Trial

5-Fluorouracil (5FU) is proven to be the most effective therapy in field directed treatment for AK, with Jansen et al. reporting a 1-year probability of treatment success of 74.7%. However, treatment with 5FU is associated with side effects, like erythema, itching, a burning sensation and crusting, and a burdensome dosing regimen of twice daily application for four weeks. This long treatment duration in combination with side-effects and overall lifestyle adjustments during treatment can be the reason for poor adherence and premature termination, and it can also lead to future refusal of 5FU therapy. Therefore, room for improvement lies in increasing the tolerability, in terms of side effects or treatment duration, while maintaining the efficacy of 5FU in the treatment of AK.

Addition therapy, which can shorten the duration of treatment, might be the key to success. Calcipotriol (CAL) enhances thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, which promotes antitumor immunity. Therefore, it is known to have a synergistic effect when combined with 5FU in the treatment of AK. This suggests that short-term treatment with 5FU-CAL is effective and provides the opportunity to shorten duration of treatment, thereby improving tolerability of treatment and full adherence to the treatment regimen.

However, no study compared 5FU-CAL combination therapy with standard 5FU treatment for a duration of 28 days. This study aims to evaluate whether a short course of combination therapy with 5FU-CAL is non-inferior to a full course of 5FU monotherapy with respect to the 1-year probability of treatment success.

Study Overview

• Status: Recruiting
• Conditions: Actinic Keratoses
• Intervention / Treatment: Drug: 5FU-Calcipotriol; Drug: 5-FU 50 MG/ML Topical Cream

• Study Type: Interventional
• Enrollment (Estimated): 232
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Myrthe MG Moermans, MD; Phone Number: 0031433877295; Email: myrthe.moermans@mumc.nl

Study Locations

• Netherlands
  • Brabant
    • Eindhoven, Brabant, Netherlands, 5623 EJ
      • Recruiting
      • Catharina Hospital Eindhoven
      • Contact: Myrthe MG Moermans, MD; Phone Number: 0031433877295; Email: myrthe.moermans@mumc.nl
  • Limburg
    • Heerlen, Limburg, Netherlands, 6419 HC
      • Recruiting
      • Zuyderland Medical Center
      • Contact: Myrthe MG Moermans, MD; Phone Number: 0031433877295; Email: myrthe.moermans@mumc.nl
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Recruiting
      • Maastricht University Medical Center
      • Contact: Myrthe MG Moermans, MD; Phone Number: 0031433877295; Email: myrthe.moermans@mumc.nl
    • Venlo, Limburg, Netherlands, 5912 BL
      • Recruiting
      • VieCuri Medical Center
      • Contact: Myrthe MG Moermans, MD; Phone Number: 0031433877295; Email: myrthe.moermans@mumc.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adults above 18 years of age

• Clinical and dermoscopical diagnosis of AK by a dermatologist, in one or more area(s):

  • Face, ears, (balding) scalp
  • Neck/Shawl area, including the sun-exposed chest area
  • Upper extremities
• Number of AK lesions ≥4 in a continuous treatment area of up to 100 cm2
• AK Olsen grade I-III

Exclusion Criteria:

• Previous field treatment for AK within 2cm of the treatment area, within 3 months
• (non) melanoma skin cancer in treatment area
• Mucosal lesions
• Genetic skin cancer disorder
• Women who are pregnant or breastfeeding
• Women of childbearing potential, who are not willing to use effective contraceptive measures
• Previous allergy or intolerance to either 5FU or calcipotriol
• Patients with known contra-indications for calcipotriol use: previous diagnosis of hyper-calcemia, disturbed calcium metabolism, severe kidney or liver dysfunction
• Concurrent use of oral capecitabine or any other topical or systemic chemopreventive agent for any indication
• Concurrent use of other topical treatments registered as treatment for AK
• Limited understanding of the Dutch language and not being able to give informed consent (incapacitated patients)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: topical 5FU-CAL, twice daily, during 4 or 6 consecutive days; Treatment duration is based on treatment location	Drug: 5FU-Calcipotriol; topical 5FU-CAL, twice daily, during 4 or 6 consecutive days, depending on the treatment location
Active Comparator: topical 5FU, twice daily, 7 days a week, during 4 weeks	Drug: 5-FU 50 MG/ML Topical Cream; topical 5FU, twice daily, 7 days a week, during 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment success at 12 months post-treatment	Treatment success at 12 months post treatment, defined as ≥75% reduction in the number of AK lesions in the treatment area (partial clearance)	12 months after finishing treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AK clearance rate	mean percentage change in AK lesions at 3 and 12 months post-treatment	3 and 12 months after finishing treatment
Recurrence rate	New lesions and need for retreatment at 3 and 12 months post-treatment	3 and 12 months after finishing treatment
Adverse effects	Patients experiencing moderate to severe adverse effects	During treatment and 3 months post-treatment
Treatment compliance	Patients who are fully compliant to the prescribed treatment regimen (5FU-CAL or 5FU monotherapy)	During treatment
Patient satisfaction	Patients who express to be satisfied with their treatment	3 and 12 months post-treatment
Quality of life before, during and after treatment	The mean score for quality of life on the Skindex-17 questionnaire. The Skindex-17 questionnaire has 17 items investigating the quality of life on different domains. The questions are answered on a five-point scale. A higher score represents a higher impact on QoL.	Baseline, 1 week after finishing treatment and 3 and 12 months post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term risk for cSCC	The long-term probability of developing a cSCC	at least 3 years post-treatment

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2024
• Primary Completion (Estimated): March 2, 2029
• Study Completion (Estimated): March 2, 2029

Study Registration Dates

• First Submitted: July 5, 2024
• First Submitted That Met QC Criteria: July 5, 2024
• First Posted (Actual): July 12, 2024

Study Record Updates

• Last Update Posted (Actual): May 11, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: 5-Fluorouracil; Calcipotriol
• Additional Relevant MeSH Terms: Neoplasms; Skin Diseases; Precancerous Conditions; Keratosis, Actinic; Keratosis; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Fluorouracil; Calcipotriene
• Other Study ID Numbers: 2024-511409-42-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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