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

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

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.

Study Overview

• Status: Completed
• Conditions: Precancerous Condition
• Intervention / Treatment: Other: placebo; Drug: perillyl alcohol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Other: placebo; Applied as topical cream
Experimental: Low Dose POH 0.30%; 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; Applied as topical cream
Experimental: High Dose POH 0.76%; 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; Applied as topical cream

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: National Cancer Institute (NCI); Arizona Disease Control Research Commission
• Investigators: Study Chair: Steve Stratton, PhD, University of Arizona

Study record dates

Study Major Dates

• Study Start: May 1, 2004
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: February 5, 2008
• First Submitted That Met QC Criteria: February 5, 2008
• First Posted (Estimate): February 6, 2008

Study Record Updates

• Last Update Posted (Estimate): April 1, 2015
• Last Update Submitted That Met QC Criteria: March 27, 2015
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: actinic keratosis
• Additional Relevant MeSH Terms: Neoplasms; Precancerous Conditions; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Perillyl alcohol
• Other Study ID Numbers: CDR0000582634; P30CA023074 (U.S. NIH Grant/Contract); P01CA027502 (U.S. NIH Grant/Contract); UARIZ-HSC-04-27 (Other Identifier: UA IRB no.); UARIZ-POH-002 (Other Identifier: NCI)