Other Benign Neoplasm of Skin, Unspecified
Conditions
Keywords
skin cancer
Brief summary
RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming. The use of eflornithine and diclofenac may stop cancer from growing in patients with sun-damaged skin. PURPOSE: This randomized phase II trial is studying the side effects and how well eflornithine works compared with diclofenac, given alone or together, in treating patients with sun-damaged skin.
Detailed description
OBJECTIVES: Primary * To determine if combination therapy with topical eflornithine hydrochloride ointment and topical diclofenac sodium gel over 3-months increases the efficacy versus either agent used alone in the treatment of moderately sun-damaged skin. Secondary * To evaluate the safety of sequential administration of topical eflornithine hydrochloride ointment and topical diclofenac sodium gel. * To determine the correlation of karyometric changes with histopathologic, immunohistochemical, clinical, and genetic polymorphism data. * To obtain materials for microarray analysis. OUTLINE: Patients are randomized to 1 of 3 treatment arms. * Eflornithine hydrochloride : Patients apply topical eflornithine hydrochloride ointment to their left forearm twice daily on days 1-90. * Diclofenac sodium : Patients apply topical diclofenac sodium gel to their left forearm once daily on days 1-90. * Eflornithine hydrochloride/Diclofenac sodium : Patients apply topical eflornithine hydrochloride ointment as in arm I twice daily and topical diclofenac sodium gel as in arm II once daily on days 1-90. Prior to treatment, three 4-mm punch biopsies are taken from the skin of the left lateral forearm for assessment of histopathology, the cyclooxygenase-2 enzyme and p53 expression, apoptosis, and nuclear chromatin karyometry. Tissue is also obtained for future use in microarray analysis. Blood is drawn for assessment of ornithine decarboxylase polymorphisms and for banking for subsequent studies. Biopsies are repeated 2-3 weeks after completion of treatment. Digital photographs are taken at baseline and 1-2 weeks after completion of study therapy to document improvement of sun damage, appearance of new skin lesions, and toxicity.
Interventions
DRUGDiclofenac Na gel
Given topically twice daily on days 1-90
DRUGEflornithine HCL ointment
Given topically twice daily on days 1-90
Sponsors
National Cancer Institute (NCI)
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Visible sun-induced damage to the skin as assessed by the study dermatologists * No inflammation of the skin on the lateral forearms * No more than 10 actinic keratoses on the left forearm, and no actinic keratoses in the treatment area * Resident of Pima or an adjoining Southern Arizona county * History of treated basal cell carcinoma and/or squamous cell carcinoma of the skin at any site other than the left forearm allowed if excision or topical treatment was completed more than 30 days ago (60 days for radiotherapy) * History of treated basal cell carcinoma and/or squamous cell carcinoma of the skin on the left forearm allowed 6 months after treatment is completed * Must agree to avoid sun exposure to the left forearm as much as possible * Not pregnant or nursing * Not moderately to highly immunosuppressed by virtue of medication or disease, except for mildly suppressive disorders (e.g., diabetes mellitus or on mildly immunosuppressive therapy such as inhaled steroids for asthma) * No serious concurrent illness that could interfere with study participation * No active peptic ulcer disease, bleeding disorder, renal failure (creatinine \> 2.0 mg/dL), or porphyria * No known hypersensitivity to diclofenac sodium, eflornithine, acetylsalicylic acid, or NSAIDS * No evidence of serious underlying medical conditions as demonstrated by abnormal values on baseline laboratory assessment * More than 6 months since prior chemotherapy and in complete remission * More than 60 days since prior and no concurrent oral diclofenac sodium (Cataflam®, Voltaren®, Voltaren-XR®) or combination of diclofenac and misoprostol (Arthrotec®) * More than 60 days since prior and no concurrent IV eflornithine hydrochloride * More than 30 days since prior and no concurrent topical retinoids, steroids, imiquimod (Aldara®), aminolevulinic acid HCl (Levulan®), eflornithine (Vaniqa®), diclofenac sodium gel (Solaraze®), or fluorouracil at any site * More than 30 days since prior and no concurrent topical medication, other than emollients or sunscreens, on the left forearm * Not undergoing concurrent bone marrow or solid organ transplant * No concurrent immunosuppressive therapy (e.g., systemic chemotherapy or rheumatologic agents such as infliximab \[Remicade®\]) * No concurrent sunscreen use to the left forearm * No concurrent active therapy for any invasive cancer * No concurrent NSAIDs for more than 14 days per month for arthritic and other pain conditions * Concurrent prednisone or other steroids with doses up to 20 mg/day (or the equivalent dose) allowed * At least 30 days since prior and no concurrent enrollment on other investigational drug or device trial
Exclusion criteria
* Individuals receiving concurrent topical therapy with retinoids, steroids, 5-fluorouracil, Levulan, Vaniqa (eflornithine), Solaraze, or Imiquimod (Aldara®) within 30 days prior to study enrollment will be excluded. Subjects may be reconsidered for eligibility 30 days after the last topical treatment. * Individuals who have had treatment for basal cell carcinoma or squamous cell carcinoma of the skin of the left forearm within six months prior to evaluation for the study will not be eligible. If interested, these subjects will be encouraged to return for re-evaluation once the six-month period is over. * Individuals who are moderately to highly immunosuppressed by virtue of medication or disease will not be allowed to participate. This category includes individuals undergoing bone marrow or solid organ transplant, or receiving immunosuppressive therapy such as systemic chemotherapy or rheumatologic agents such as infliximab (Remicade®). However, individuals with mildly suppressive disorders such as diabetes mellitus or on mildly immunosuppressive therapy such as inhaled steroids for asthma will be eligible for participation. Doses up to 20 mg of prednisone per day or the equivalent dose of other steroids will be allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Putrescine Over 3 Months | 3 months | Putrescine is measured in nmole/g skin per biopsy. Baseline and End of Study biopsies were measured and the change was produced by subtracting baseline levels from End of Study levels. There was one baseline biopsy and one End of Study biopsy per participant. |
| Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | 3 months | Adverse events were compared across three treatment groups by severity determined by the clinician. All adverse events were resolved by the end of follow up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Histologic Score Diagnosis and Treatment Group | 3 months | Change scores were computed by subtracting baseline histologic score from End of Study histologic score. Slides were formalin fixed. Histologic Score has been developed by this research group over the course of Grant (reference below). A standardized form captures data on the following criteria: basal or suprabasilar pleomorphism (atypia); inflammation; hyperkeratosis; parakeratosis. The atypia and inflammation were rated as: none (0), mild to moderate(1), and severe (2). The remaining criteria were rated as present (1) or absent (0). Histologic Scores were computed by adding together the codes for the histologic criteria. Higher scores reflected higher level of epidermal /dermal damage. |
Countries
United States
Participant flow
Recruitment details
184 participants were accrued. 18 were accrued when an interim analyses resulted in a change in formulation and dosing. The primary analyses is based on 166 accrued after this change.
Pre-assignment details
166 participants were accrued after the change in formulation. 10 participants were not randomized for various reasons. 156 participants were randomized to one of the 3 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients apply topical eflornithine hydrochloride ointment to their left forearm twice daily on days 1-90. | 52 |
| Arm II Patients apply topical diclofenac sodium gel to their left forearm once daily on days 1-90. | 52 |
| Arm III Patients apply topical eflornithine hydrochloride ointment as in arm I twice daily and topical diclofenac sodium gel as in arm II once daily on days 1-90. | 52 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 | 2 |
| Overall Study | change in eligibility status | 0 | 1 | 1 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | intercurrent illness | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 7 |
Baseline characteristics
| Characteristic | Total | Arm I | Arm II | Arm III |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 54 Participants | 15 Participants | 17 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 102 Participants | 37 Participants | 35 Participants | 30 Participants |
| Age, Continuous | 60.4 years STANDARD_DEVIATION 10.2 | 59.3 years STANDARD_DEVIATION 9.5 | 60.4 years STANDARD_DEVIATION 11 | 61.4 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 156 participants | 52 participants | 52 participants | 52 participants |
| Sex: Female, Male Female | 112 Participants | 37 Participants | 37 Participants | 38 Participants |
| Sex: Female, Male Male | 44 Participants | 15 Participants | 15 Participants | 14 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 | 20 / 52 | 45 / 52 | 28 / 52 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 | 0 / 52 |
Outcome results
Primary
Changes in Putrescine Over 3 Months
Putrescine is measured in nmole/g skin per biopsy. Baseline and End of Study biopsies were measured and the change was produced by subtracting baseline levels from End of Study levels. There was one baseline biopsy and one End of Study biopsy per participant.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eflornithine Hydrochloride | Changes in Putrescine Over 3 Months | 0.03 nmol/g skin | Standard Error 1.12 |
| Diclofenac Sodium | Changes in Putrescine Over 3 Months | 1.45 nmol/g skin | Standard Error 1.23 |
| Eflornithine Hydrochloride/Diclofenac Sodium | Changes in Putrescine Over 3 Months | 0.2 nmol/g skin | Standard Error 0.96 |
Primary
Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months
Adverse events were compared across three treatment groups by severity determined by the clinician. All adverse events were resolved by the end of follow up.
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging None | 48 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and stinging Mild | 4 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | burning and stinging Moderate | 0 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging Severe | 0 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis None | 42 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Mild | 9 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Moderate | 1 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Severe | 0 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-None | 46 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Moderate | 1 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Severe | 0 participants |
| Eflornithine Hydrochloride | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Mild | 5 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Severe | 0 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Mild | 10 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and stinging Mild | 8 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Severe | 1 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Moderate | 6 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | burning and stinging Moderate | 0 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Mild | 12 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging None | 44 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging Severe | 0 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-None | 34 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Moderate | 8 participants |
| Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis None | 33 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-None | 40 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Moderate | 5 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Mild | 6 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging None | 48 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Moderate | 6 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis Severe | 0 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Severe | 0 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Pruritis None | 40 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and stinging Mild | 3 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Rash, Redness. Erythema-Mild | 7 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | burning and stinging Moderate | 1 participants |
| Eflornithine Hydrochloride/Diclofenac Sodium | Safety of Combination Therapy With Topical Eflornithine Hydrochloride Ointment and Topical Diclofenac Sodium Gel Over 3-months | Burning and Stinging Severe | 0 participants |
p-value: 0.022Fisher Exact
Secondary
Change in Histologic Score Diagnosis and Treatment Group
Change scores were computed by subtracting baseline histologic score from End of Study histologic score. Slides were formalin fixed. Histologic Score has been developed by this research group over the course of Grant (reference below). A standardized form captures data on the following criteria: basal or suprabasilar pleomorphism (atypia); inflammation; hyperkeratosis; parakeratosis. The atypia and inflammation were rated as: none (0), mild to moderate(1), and severe (2). The remaining criteria were rated as present (1) or absent (0). Histologic Scores were computed by adding together the codes for the histologic criteria. Higher scores reflected higher level of epidermal /dermal damage.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eflornithine Hydrochloride | Change in Histologic Score Diagnosis and Treatment Group | 0.33 units on a scale | Standard Error 0.15 |
| Diclofenac Sodium | Change in Histologic Score Diagnosis and Treatment Group | 0.26 units on a scale | Standard Error 0.13 |
| Eflornithine Hydrochloride/Diclofenac Sodium | Change in Histologic Score Diagnosis and Treatment Group | 0.64 units on a scale | Standard Error 0.18 |