Investigational drugs currently in phase II clinical trials for actinic keratosis

ABSTRACT

Introduction: Actinic keratoses (AKs) are limited areas of irregular epidermal growth on a background of excessive solar exposure. The entire sun-damaged skin is considered a field of cancerization with multiple visible and subclinical lesions. AK management requires field-directed therapies to block lesion relapse and prevent squamous cell carcinoma (SCC).

Areas covered: In this review, we focused on phase II clinical trials for AKs, involving well-known agents and newer molecules such as proapoptotic drugs (VDA-1102, SR-T100, oleogel-S10, ICVT, eflornithine), immunomodulants (isotretinoin, tretinoin) and chemopreventive agents (nicotinamide, perillyl alcohol, liposomal T4N5). We used the website ‘ClinicalTrials.Gov’ as main reference. We selected and discussed completed and ongoing trials and analysed chemical structure and mechanism of action of the investigated molecules.

Expert opinion: AK therapy should be tailored on the patient’s profile considering first of all the age and site of the AKs, which are relevant parameters for local immune response. The new molecules could be combined to obtain a synergic effect blocking the different steps of skin tumorigenesis. Phase II trials highlight a new therapeutic opportunity to block selectively cell proliferation regulators and work both on the field of cancerization and on the AKs currently present.

Trial registration: ClinicalTrials.gov identifier: NCT02239679.

Trial registration: ClinicalTrials.gov identifier: NCT01475955.

Trial registration: ClinicalTrials.gov identifier: NCT01458587.

Trial registration: ClinicalTrials.gov identifier: NCT02632110.

Trial registration: ClinicalTrials.gov identifier: NCT02628236.

Trial registration: ClinicalTrials.gov identifier: NCT00002975.

Trial registration: ClinicalTrials.gov identifier: NCT02799030.

Trial registration: ClinicalTrials.gov identifier: NCT02149342.

Trial registration: ClinicalTrials.gov identifier: NCT01583816.

Trial registration: ClinicalTrials.gov identifier: NCT01998984.

Trial registration: ClinicalTrials.gov identifier: NCT01820260.

Trial registration: ClinicalTrials.gov identifier: NCT01803477.

Trial registration: ClinicalTrials.gov identifier: NCT00852137.

Trial registration: ClinicalTrials.gov identifier: NCT00239135.

Trial registration: ClinicalTrials.gov identifier: NCT00700063.

Trial registration: ClinicalTrials.gov identifier: NCT00375739.

Trial registration: ClinicalTrials.gov identifier: NCT00107965.

Trial registration: ClinicalTrials.gov identifier: NCT00427050.

Trial registration: ClinicalTrials.gov identifier: NCT00544297.

Trial registration: ClinicalTrials.gov identifier: NCT01358851.

Trial registration: ClinicalTrials.gov identifier: NCT02654717.

Trial registration: ClinicalTrials.gov identifier: NCT03116698.

Trial registration: ClinicalTrials.gov identifier: NCT03538951.

Trial registration: ClinicalTrials.gov identifier: NCT02844777.

Trial registration: ClinicalTrials.gov identifier: NCT02085395.

Trial registration: ClinicalTrials.gov identifier: NCT00786994.

Trial registration: ClinicalTrials.gov identifier: NCT03684772.

Trial registration: ClinicalTrials.gov identifier: NCT02278861.

Trial registration: ClinicalTrials.gov identifier: NCT00021294.

Trial registration: ClinicalTrials.gov identifier: NCT00608634.

Trial registration: ClinicalTrials.gov identifier: NCT00089180.

Trial registration: ClinicalTrials.gov identifier: NCT03210740.

Trial registration: ClinicalTrials.gov identifier: NCT00005097.

KEYWORDS:

• Actinic keratosis
• investigational drugs
• phase II clinical trials

Article Highlights

• AKs are dysplastic keratinocyte lesions, occurring in chronically photodamaged skin and represent an important risk factor for the development of SCC.

• The best treatment modalities act on the pathogenesis of AKs and their field of cancerization to obtain long-term control of lesions and avoid AK progression to aggressive SCC.

• A substantial number of phase II studies for AK evaluated new dosage and schedules of treatment, as well as new formulations of molecules already used in the clinical practice, with the aim of increasing their efficacy and reducing the AEs.

• Attention should be placed on new molecules and therapeutic strategies that have an impact on the pathogenesis of AK, and therefore require further investigation to pursue a preventive action.

• Combined and sequential treatments can be considered to improve clinical efficacy and reduce AEs, leading to a better patient compliance.

• To date, a therapeutic algorithm based on patient phenotype has not been established yet. It appears important to adapt the therapies on the patient phenotype and possible multimorbity. In this regard, particular attention should be placed on the immune status of the patient.

This box summarizes key points contained in the article.

Acknowledgments

We wish to thank Prof. Denis Mariano for technical editing assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

One reviewer is an investigator on the clinical trial NCT01803477. One referee has served as a Consultant on the Advisory Board for- and has received honoraria from Leo Pharma, Almirall-Hermal, Galderma and Biofrontera. They have received honoraria for lectures from Almirall-Hermal, Leo Pharma and Galderma. Their institution has also received a grant from Leo Pharma, Galderma and Biofrontera and personal travel fees from Leo Pharma and Galderma. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.