Topical Perillyl Alcohol in Treating Patients With Sun Damaged Skin and Actinic Keratoses

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as perillyl alcohol, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. It is not yet known which dose of topical perillyl alcohol is more effective in stopping the development of cancer in sun damaged skin. PURPOSE: This randomized phase II trial is studying high-dose topical perillyl alcohol to see how well it works compared with low-dose topical perillyl alcohol in treating patients with sun damaged skin and actinic keratoses.

Detailed Description
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OBJECTIVES: Primary To determine if topical administration of perillyl alcohol (POH) cream can reverse actinic damage as evidenced by normalization of quantitative skin histopathology scores in skin tissue biopsy samples from patients with moderate to severe sun damage. Secondary To determine if topical POH can be administered safely to the forearms of these patients. OUTLINE: Patients are randomized to 1 of 3 arms. Placebo: Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. Low Dose: Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. High Dose: Patients apply POH cream (0.76%) as in arm II. Patients undergo tissue sampling of the right or left dorsal forearm and of physician-selected representative actinic keratoses (AK) at baseline and after completion of study therapy. Tissue samples are assessed for changes in patterns of biomarker expression (i.e., p53, apoptosis, c-Fos histopathology) and karyometry. After completion of study therapy, patients undergo tissue sampling of the opposite forearm as well as blood sample collection to determine perillyl alcohol (POH) levels in blood and biopsy samples. Urine is also collected and analyzed for safety at the end of treatment. Digital photographs of the forearms and hands are obtained at baseline and after 3 months of study treatment. Optical coherence tomography imaging is also performed on pre- and post-biopsy sites to quantify the effect of POH on sun damage and AK in skin. After completion of study treatment, patients are followed monthly.

Official Title
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Phase 2a Randomized, Placebo-Controlled, Double-Blind Trial of Topical Perillyl Alcohol in Sun Damaged Skin

Conditions
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Precancerous Condition

Intervention / Treatment
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* Drug: perillyl alcohol
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Resident of Pima or adjoining Southern Arizona county Patients outside of Pima County are also eligible Sun damaged skin as judged by the study physician and quantifiable, clinically diagnosed, and visible actinic keratoses (AK) on both dorsal forearms, with at least two AK on each arm AK lesions must not be clustered, confluent, or too numerous to count accurately Presence of AK on sites other than the test area allowed No significant inflammation or irritation of the skin of the upper extremities that is not clinically diagnosed as sun damage or AK Patients must agree to limit sun exposure as much as possible and may continue their normal pattern of sunscreen use PATIENT CHARACTERISTICS: Inclusion criteria: Females must not be of childbearing potential, and therefore must be post-menopausal or surgically sterile by hysterectomy Not pregnant or nursing Exclusion criteria: Concurrent skin malignancy or disorder of the upper extremities Patients with Squamous cell carcinoma or basal cell carcinoma in an area other than the test area are eligible upon excision of the Squamous cell carcinoma or basal cell carcinoma Patients who are immunosuppressed by virtue of medication or disease Serious concurrent illness that could interfere with study regimen Invasive cancer within the past 5 years PRIOR CONCURRENT THERAPY: At least 30 days since prior topical medications to the skin of the upper extremities except for emollients or sunscreens At least 30 days since prior and no concurrent mega-doses of vitamins, defined as any of the following: More than 5 times the recommended daily allowance More than 5 capsules of multivitamins 400 IU of vitamin E 200 μg of selenium 1 gm of vitamin C At least 6 months since prior and no concurrent therapy for squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) anywhere in the test area (i.e., the forearms or hands) Treatment for Squamous cell carcinoma or basal cell carcinoma on sites other than the test area is allowed At least 4 weeks since prior surgical biopsy, surgical excision, or cryotherapy for AK in the test area and the sites must have healed At least 6 months since prior topical treatment (e.g., 5-fluorouracil or imiquimod) for AK No concurrent therapy that may interfere with clinical evaluations No concurrent topical drug treatment (e.g., retinoids, aminolevulinic acid, diclofenac sodium, imiquimod, or fluorouracil) to any area of skin, including test area No concurrent enrollment in another clinical trial No concurrent topical citrus peel or consumption of citrus peel No chemotherapy for cancer within the past 5 years

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. | Other: placebo<br>* Applied as topical cream<br>|
| Experimental: Low Dose POH 0.30%<br>Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. | Drug: perillyl alcohol<br>* Applied as topical cream<br>|
| Experimental: High Dose POH 0.76%<br>Patients apply perillyl alcohol (POH) cream (0.76%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. | Drug: perillyl alcohol<br>* Applied as topical cream<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Histopathology Score of Sun Damaged Skin by Treatment Group | The histopathologic scoring for skin biopsies from sun-damaged skin to assess the following seven characteristics: 1- atypia (levels 0, 1 & 2), 2- inflammation (grades 0, 1 & 2), 3- hyperkeratosis (loss of basket weave pattern of stratum corneum), 4- parakeratosis (present when there were >3 characteristic nuclei per 40:1 field in stratum corneum), 5- dyskeratosis (focal presence of cells with homogenous, pink cytoplasm n pyknotic nuclei), 6- epidermotropism (lymphocytes migration of >3 cells into epidermis, 7- loss of granular layer. All assessments were done using a 40:1 objective. | Baseline to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | The events do not have to be caused by the drug or therapy, and they may be mild, moderate, or severe. (NCI) | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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actinic keratosis