Precancerous Condition
Conditions
Keywords
actinic keratosis
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.
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.
Interventions
DRUGperillyl alcohol
Applied as topical cream
OTHERplacebo
Applied as topical cream
Sponsors
National Cancer Institute (NCI)
Arizona Disease Control Research Commission
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients apply a placebo cream topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. | 28 |
| Arm II Patients apply perillyl alcohol (POH) cream (0.3%) topically to each dorsal forearm twice daily for 3 months in the absence of unacceptable toxicity. | 27 |
| Arm III Patients apply POH cream (0.76%) as in arm II. | 28 |
| Total | 83 |
Baseline characteristics
| Characteristic | Arm II | Arm III | Arm I | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 15 Participants | 14 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 13 Participants | 14 Participants | 37 Participants |
| Age, Continuous | 68.8 years STANDARD_DEVIATION 10.6 | 67.6 years STANDARD_DEVIATION 10.9 | 66.9 years STANDARD_DEVIATION 9.9 | 67.7 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 27 participants | 28 participants | 28 participants | 83 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 8 Participants | 20 Participants |
| Sex: Female, Male Male | 20 Participants | 23 Participants | 20 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 28 | 14 / 27 | 15 / 28 |
| serious Total, serious adverse events | 4 / 28 | 5 / 27 | 1 / 28 |
Outcome results
Primary
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.
Time frame: Baseline to 3 months
Population: change in histopathological scoring was calculated only for participants with baseline and end of study measurements. (n=79)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Histopathology Score of Sun Damaged Skin by Treatment Group | 0.4 units on a scale | Standard Deviation 1.3 |
| Low Dose POH 0.30% | Change in Histopathology Score of Sun Damaged Skin by Treatment Group | -0.1 units on a scale | Standard Deviation 1.3 |
| High Dose POH 0.76% | Change in Histopathology Score of Sun Damaged Skin by Treatment Group | 0.1 units on a scale | Standard Deviation 1.4 |
p-value: 0.1Wilcoxon (Mann-Whitney)
p-value: 0.41Wilcoxon (Mann-Whitney)
Secondary
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)
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No rash, redness, erythema | 16 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No flaking, crusting | 23 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No burning or stinging | 25 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No pruritus | 22 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild rash, redness, erythema | 11 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild flaking, crusting | 5 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild burning or stinging | 2 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild pruritus | 6 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate rash, redness, erythema | 1 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate flaking, crusting | 0 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate burning or stinging | 1 participants |
| Placebo | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate pruritus | 0 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate pruritus | 1 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No rash, redness, erythema | 12 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild burning or stinging | 3 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate rash, redness, erythema | 1 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No flaking, crusting | 20 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild flaking, crusting | 7 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate burning or stinging | 0 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No burning or stinging | 24 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild pruritus | 3 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild rash, redness, erythema | 14 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No pruritus | 23 participants |
| Low Dose POH 0.30% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate flaking, crusting | 0 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No pruritus | 23 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild rash, redness, erythema | 15 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate flaking, crusting | 1 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild flaking, crusting | 4 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild burning or stinging | 1 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Mild pruritus | 4 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate burning or stinging | 0 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No rash, redness, erythema | 13 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No flaking, crusting | 23 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate rash, redness, erythema | 0 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | No burning or stinging | 27 participants |
| High Dose POH 0.76% | Skin Related Events From Perillyl Alcohol at Administered Doses by Participants | Moderate pruritus | 1 participants |
p-value: >0.05Chi-squared