Biological Effects of LEO 43204 in Actinic Keratosis

Study Overview
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Brief Summary
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This is a Phase I, single-centre, open label, within-subject comparison trial to explore the biological effects of LEO 43204 Gel, 0.037%, applied once daily for 3 consecutive days in patients with actinic keratosis on the upper extremity. The treatment area for each patient will be as defined as a contiguous area of 250 cm2 of skin on the upper extremity (including the dorsum manus) that contains a minimum of 5 AK lesions. Additionally there must be at least one AK lesion located in a non-treated area on the contralateral arm. All eligible subjects will receive LEO 43204 Gel, 0.037%, on the treatment area on Days 1, 2 and 3. Study medication application will be (sub)investigator applied. A total of 30 patients will be enrolled into this study (n=15 in each of the two groups). Patients will be divided into two groups with different biopsy schedules.

Official Title
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Biological Effects of LEO 43204 in Actinic Keratosis Assessed by Histopathology

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: LEO 43204 Gel, 0.037%
* Drug: LEO 43204 Gel, 0.037%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Signed and dated informed consent has been obtained. 2. Subjects with at least 5 non-keratotic, clinically typical, visible and discrete AK lesions within a contiguous 250 cm2 area (AK Treatment Area) on the upper extremity, 3. Subjects with one additional AK lesion located on the contralateral arm. 4. Subjects with an area of normal skin in close proximity to the AK Treatment Area or on the contralateral arm. 5. Male and female subjects, 18 years or older. 6. Agreement from the patient to allow photographs of the selected treatment area to be taken and used as part of the study data package 7. Ability to follow study instructions and likely to complete all study requirements 8. Female Subjects must be of either non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus or has tubal litigation) or, child-bearing potential* provided there is a confirmed negative pregnancy test prior to trial treatment to rule out pregnancy. Female subjects are considered of child-bearing potential unless they have had a hysterectomy or have undergone tubal litigation or have been post-menopausal for at least one year prior to first visit. 9. Female subjects of child-bearing potential must be willing to use effective contraception at trial entry and until completion. Effective contraception is defined as follows: Abstinence (when this is in line with the preferred and usual life style of the subject). Vasectomised partner (given that the subject is monogamous). An intrauterine device. Double barrier method defined as two distinct methods (two actual barrier methods). Hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal ring, percutaneous contraceptive patches, implants and injectables) for at least one menstrual cycle prior to enrolment. Exclusion Criteria: 1. Prior treatment with ingenol mebutate gel in the treatment area within the last 12 months. 2. Previously assigned treatment in this clinical trial or previously participated in a clinical trial in the LEO 43204 programme (presently LP0084-68, LP0084-1013, LP0084-1014, LP0084-1015, LP0084-1148, LP0084-1077, LP0084-1193, LP0084-1194, LP0084-1195, LP0084-1196). 3. Location of the selected treatment area within 5 cm of an incompletely healed wound or infected area of the skin (excl. study related biopsies) or within 5 cm of a suspected basal cell carcinoma (BCC) or SCC. 4. History or evidence of skin conditions other than the study indication that would interfere with the histologically- or biomarker evaluation of the study medication (e.g. eczema, unstable psoriasis, xeroderma pigmentosum). 5. Treatment area lesions that have an atypical clinical appearance (e.g. hypertrophic, hyperkeratotic, recalcitrant disease [had cryosurgery on two previous occasions] and/or cutaneous horns). 6. Known sensitivity or allergy to any of the ingredients of LEO 43204 Gel (e.g. citric acid) 7. Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety during the course of the study, as determined by Investigator clinical judgment. 8. Anticipated need for in-patient hospitalisation or in-patient surgery during the study period. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in the Prohibited Therapies or Medications (listed below). 9. Anticipated excessive or prolonged exposure to ultraviolet light (e.g. sunlight) or use of tanning beds for the duration of the study 10. Current participation in any other interventional clinical trial 11. Subjects who have received treatment with any non-marketed drug product (i.e. an agent which has not yet been made available for clinical use following registration) within the last two months. 12. Subjects known to be infected with Human Immunodeficiency Virus (HIV). 13. Subject known or, in the opinion of the investigator, is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state). 14. Females who are pregnant, of child-bearing potential and wishing to become pregnant during the trial, or are breast feeding. 15. Females of child-bearing potential with positive pregnancy test at [screening or visit 1]. 16. Previous enrolment in this clinical trial. Prohibited Therapies and/or Medications: within 2 weeks prior to the Screening visit 17. Cosmetic or therapeutic procedures (e.g. use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing): within 2 cm of the selected treatment areas and within 2 cm of the selected AK lesion outside the treatment area 18. Use of acid-containing therapeutic products (e.g. salicylic acid or fruit acids, such as alpha and beta hydroxy acids and glycolic acids), topical retinoids or light chemical peels: within 2 cm of the selected treatment areas and within 2 cm of the selected AK lesion outside the treatment area 19. Use of topical salves (non-medicated/non-irritant lotion/cream are acceptable) or topical steroids: within 2 cm of the selected treatment areas and within 2 cm of the selected AK lesion outside the treatment area; artificial tanners: within 5 cm of the selected treatment areas and within 5 cm of the selected AK lesion outside the treatment area Prohibited Therapies and/or Medications: within 4 weeks prior to the Screening visit 20. Treatment with immunomodulators (e.g. azathioprine), cytotoxic drugs (e.g. cyclophosphamide, vinblastine, chlorambucil, methotrexate, podophyllin, camptothecin) or interferon/interferon inducers. 21. Treatment with systemic medications that suppress the immune system (e.g. cyclosporine, prednisone, methotrexate, infliximab). 22. Treatment/therapy with UVB Prohibited Therapies and/or Medications: within 8 weeks prior to the Screening visit 23. Treatment with 5-FU, imiquimod, diclofenac, or photodynamic therapy: within 2 cm of the selected treatment areas and within 2 cm of the selected AK lesion outside the treatment area Prohibited Therapies and/or Medications: within 6 months prior to the Screening visit 24. Use of systemic retinoids (e.g. isotretinoin, acitretin, bexarotene)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEO 43204 Group A<br>Group A - Experimental LEO 43204, applied once daily for 3 consecutive days in patients with actinic keratosis | Drug: LEO 43204 Gel, 0.037%<br> <br> |
| Experimental: LEO 43204 Group B<br>Group B - Experimental LEO 43204, applied once daily for 3 consecutive days in patients with actinic keratosis | Drug: LEO 43204 Gel, 0.037%<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of CD3+ T lymphocytes assessed by immunohistochemistry in biopsies from AK lesions 56 days after first treatment. |  | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of infiltrating cells assessed by immunohistochemical staining |  | 8 weeks | 
| Expression of inflammatory and skin matrix modulation markers assessed by RNA expression and immunohistochemistry |  | 8 weeks | 
| Expression of ICAM-1 (marker of vascular endothelium activation) assessed by immunohistochemical staining as area of section with positive staining. |  | 8 weeks | 
| Expression of Ki-67 and K16 (markers of cell proliferation and differentiation) assessed by immunohistochemical staining as area of section with positive staining. |  | 8 weeks | 
| Expression of cleaved caspase-3 (apoptosis) assessed by immunohistochemical staining as area of section with positive staining |  | 8 weeks | 
| Necrosis of the epidermis and dermis in haematoxylin & eosin-stained sections (scored on 0-3 scale). |  | 8 weeks | 
| Number of p53 gene mutations determined by DNA sequencing in normal and AK skin and blood at baseline and in a treated AK lesion at Week 8. |  | 8 weeks |