A Study of Increasing Strengths, Safety and Efficacy of Two Formulas of LEO 43204 on the Face or the Chest in Patients With Actinic Keratosis

Study Overview
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Brief Summary
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Part 1: To identify Maximum Tolerated Dose (MTD) levels of two formulations of LEO 43204 after once daily treatment for two consecutive days Part 2: To evaluate efficacy of two formulations of LEO 43204 in two doses after once daily treatment for two consecutive days compared to vehicle formulations

Official Title
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Safety and Efficacy of Escalating Doses of Two LEO 43204 Formulations Applied Once Daily for Two Consecutive Days on Full Face or Approximately 250 cm2 (40 in2) on the Chest in Subjects With Actinic Keratosis

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: LEO 43204 Formulation 1
* Drug: LEO 43204 Formulation 2
* Drug: LEO 43204 Formulation 1 Dose X
* Drug: LEO 43204 Formulation 1 Dose Y
* Drug: LEO 43204 Formulation 2 Dose XX
* Drug: LEO 43204 Formulation 2 Dose YY
* Drug: Placebo Formulation 1
* Drug: Placebo Formulation 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Following verbal and written information about the trial, subject must provide informed consent documented by signing the Informed Consent Form (ICF) prior to any trial-related procedures. Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the face Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on either the face or within a contiguous area of approximately 250 cm2 (40 in2) on the chest Subject at least 18 years of age. Female subjects must be of either: Non-childbearing potential, i.e., have a confirmed clinical history of sterility (e.g., the subject is without a uterus or have tubal ligation), or, Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment. Female subjects of childbearing potential must use effective contraception throughout the study. Exclusion Criteria: Location of the treatment area within 5 cm (2 inches) of: an incompletely healed wound, a suspected basal or squamous cell carcinoma. Prior treatment with ingenol mebutate gel on the treatment area. Lesions in the treatment areas that have: atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions). History or evidence of skin conditions other than the trial indication that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum, Rosacea), at the investigator's discretion. Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the treatment areas. Any other disease or medical condition such as history or presence of cancer, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunological, or neurological disease or disorder, that, in the opinion of the investigator, makes the subject unsuitable to participate in the trial. Any abnormal laboratory or ECG findings that are clinically significant and would impact the safety of the subjects or the interpretation of the study results, as determined by the investigator. Anticipated need for hospitalisation or out-patient surgery during the first 15 days after the first trial medication application. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in Prohibited Therapies or Medications. Known sensitivity or allergy to any of the ingredients in the LEO 43204. Presence of acute sunburn within the treatment areas. Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial. Subjects previously randomised in the trial (Part 1 or 2). Female subjects who are breastfeeding. In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g., alcoholism, drug dependency or psychotic state).

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: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: LEO 43204 Formulation 1<br>Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 1<br> <br> |
| Experimental: Part 1: LEO 43204 Formulation 2<br>Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 2<br> <br> |
| Experimental: Part 2: LEO 43204 Formulation 1 Dose X<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 1 Dose X<br> <br> |
| Experimental: Part 2: LEO 43204 Formulation 1 Dose Y<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 1 Dose Y<br> <br> |
| Experimental: Part 2: LEO 43204 Formulation 2 Dose XX<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 2 Dose XX<br> <br> |
| Experimental: Part 2: LEO 43204 Formulation 2 Dose YY<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: LEO 43204 Formulation 2 Dose YY<br> <br> |
| Placebo Comparator: Part 2: Placebo Formulation 1<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: Placebo Formulation 1<br> <br> |
| Placebo Comparator: Part 2: Placebo Formulation 2<br>Double-Blind, Once-Daily, 2-Day Treatment | Drug: Placebo Formulation 2<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | The number of participants experiencing DLTs are tabulated by treatment group. This was used to identify the maximum tolerated dose (MTD) of LEO 43204 after once daily treatment for 2 consecutive days.The MTD was defined as the highest dose level with less than 4 out of 12 participants(cohorts 1 to 4) or less than 6 out of 18 participants(cohorts 5 and 6) experiencing a DLT DLT was defined as one or more of the following 3 LSRs: Crusting Grade 4 Erosion/Ulceration Grade 4 Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: Erythema Grade 4 Crusting Grade 3 Swelling Grade 4 Erosion/Ulceration Grade 3 Vesiculation/Pustulation Grade 3 The Local Skin Responses consists of the following 6 categories: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration. Each individual LSR category are given a numeric grade of severity from 0-4. Grade 0 being no presence and 4 being the highest grade of severity. | From Day 1 up to and including Day 8 | 
| Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) |  | At Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | Complete clearance was defined as a 100% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with complete clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with complete clearance in observed cases. | At Week 8 | 
| Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | Partial clearance was defined as at least 75% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with partial clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with partial clearance in observed cases. | At Week 8 |