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

• Sponsor: University of Arizona (Other)
• Overall Status: Completed
• CT.gov ID: NCT00608634
• Collaborator: National Cancer Institute (NCI) (NIH), Arizona Disease Control Research Commission (Other)
• Enrollment: 89
• Location: 1
• Arms: 3
• Duration (Months): 61
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Precancerous Condition	Drug: perillyl alcohol; Other: placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2a Randomized, Placebo-Controlled, Double-Blind Trial of Topical Perillyl Alcohol in Sun Damaged Skin
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Histopathology Score of Sun Damaged Skin by Treatment Group [Baseline to 3 months]

   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.

Secondary Outcome Measures

1. Skin Related Events From Perillyl Alcohol at Administered Doses by Participants [3 months]

   The events do not have to be caused by the drug or therapy, and they may be mild, moderate, or severe. (NCI)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724-5024

Sponsors and Collaborators

• University of Arizona
• National Cancer Institute (NCI)
• Arizona Disease Control Research Commission

Investigators

• Study Chair: Steve Stratton, PhD, University of Arizona

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT00608634
• Other Study ID Numbers: CDR0000582634; P01CA027502; P30CA023074; UARIZ-HSC-04-27; UARIZ-POH-002
• First Posted: Feb 6, 2008
• Last Update Posted: Apr 1, 2015
• Last Verified: Mar 1, 2014

• Keywords provided by University of Arizona: actinic keratosis
• Additional relevant MeSH terms: Precancerous Conditions; Perillyl alcohol

Study Results

Participant Flow

Arm/Group Title	Placbeo	Low Dose POH 0.30%	High Dose POH 0.76%
Arm/Group Description	Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply POH cream (0.76%) as in arm II.
Period Title: Overall Study
STARTED	28	27	28
COMPLETED	26	26	27
NOT COMPLETED	2	1	1

Baseline Characteristics

Arm/Group Title	Arm I	Arm II	Arm III	Total
Arm/Group Description	Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply POH cream (0.76%) as in arm II.	Total of all reporting groups
Overall Participants	28	27	28	83
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 50%	10 37%	13 46.4%	37 44.6%
>=65 years	14 50%	17 63%	15 53.6%	46 55.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.9 (9.9)	68.8 (10.6)	67.6 (10.9)	67.7 (10.4)
Sex: Female, Male (Count of Participants)
Female	8 28.6%	7 25.9%	5 17.9%	20 24.1%
Male	20 71.4%	20 74.1%	23 82.1%	63 75.9%
Region of Enrollment (participants) [Number]
United States	28 100%	27 100%	28 100%	83 100%

Outcome Measures

1. Primary Outcome

Title	Change in Histopathology Score of Sun Damaged Skin by Treatment Group
Description	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.
Time Frame	Baseline to 3 months

Outcome Measure Data

Analysis Population Description

change in histopathological scoring was calculated only for participants with baseline and end of study measurements. (n=79)

Arm/Group Title	Placebo	Low Dose POH 0.30%	High Dose POH 0.76%
Arm/Group Description	Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply POH cream (0.76%) as in arm II.
Measure Participants	26	26	27
Mean (Standard Deviation) [units on a scale]	0.4 (1.3)	-0.1 (1.3)	0.1 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose POH 0.30%
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose POH 0.76%
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Low Dose 0.30% POH	High Dose 0.76% POH
Arm/Group Description	Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.	Patients apply POH cream (0.76%) as in arm II.
Measure Participants	28	27	28
No rash, redness, erythema	16 57.1%	12 44.4%	13 46.4%
No flaking, crusting	23 82.1%	20 74.1%	23 82.1%
No burning or stinging	25 89.3%	24 88.9%	27 96.4%
No pruritus	22 78.6%	23 85.2%	23 82.1%
Mild rash, redness, erythema	11 39.3%	14 51.9%	15 53.6%
Mild flaking, crusting	5 17.9%	7 25.9%	4 14.3%
Mild burning or stinging	2 7.1%	3 11.1%	1 3.6%
Mild pruritus	6 21.4%	3 11.1%	4 14.3%
Moderate rash, redness, erythema	1 3.6%	1 3.7%	0 0%
Moderate flaking, crusting	0 0%	0 0%	1 3.6%
Moderate burning or stinging	1 3.6%	0 0%	0 0%
Moderate pruritus	0 0%	1 3.7%	1 3.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose POH 0.30%, High Dose POH 0.76%
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	3 months for each participant.
Adverse Event Reporting Description	Standard Questionnaire
Arm/Group Title	Placebo		Low Dose POH 0.3%		High Dose POH 0.76%
Arm/Group Description	Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.		Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.		Patients apply POH cream (0.76%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity.
All Cause Mortality
	Placebo		Low Dose POH 0.3%		High Dose POH 0.76%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Low Dose POH 0.3%		High Dose POH 0.76%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/28 (14.3%)		5/27 (18.5%)		1/28 (3.6%)
Cardiac disorders
Stent Replacement	1/28 (3.6%)	1	0/27 (0%)	0	0/28 (0%)	0
Gastrointestinal disorders
Bowel Obstruction	0/28 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Skin and subcutaneous tissue disorders
SCC in treatment area	2/28 (7.1%)	2	2/27 (7.4%)	2	0/28 (0%)	0
SCC outside of treatment area	0/28 (0%)	0	1/27 (3.7%)	1	1/28 (3.6%)	1
BCC outside of treatment area	0/28 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Melanoma	1/28 (3.6%)	1	0/27 (0%)	0	0/28 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Low Dose POH 0.3%		High Dose POH 0.76%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/28 (39.3%)		14/27 (51.9%)		15/28 (53.6%)
Skin and subcutaneous tissue disorders
Mild Rash, Redness, Erythema	11/28 (39.3%)	11	14/27 (51.9%)	14	15/28 (53.6%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.