Eflornithine and/or Diclofenac in Treating Patients With Sun-Damaged Skin

Phase IIB Study to Evaluate the Safety and Efficacy of Topical Difluoromethylornithine and Topical Diclofenac in the Treatment of Sun-Damaged Skin on the Forearm

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.

Study Overview

• Status: Completed
• Conditions: Other Benign Neoplasm of Skin, Unspecified
• Intervention / Treatment: Drug: Eflornithine HCL ointment; Drug: Diclofenac Na gel

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.

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85723
      • Veterans Affairs Medical Center - Tucson
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center
    • Tucson, Arizona, United States, 85258
      • Virginia G. Piper Cancer Center at Scottsdale Healthcare - Shea

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eflornithine HCL; Patients apply Eflornithine HCL ointment to their left forearm twice daily on days 1-90.	Drug: Eflornithine HCL ointment; Given topically twice daily on days 1-90; Other Names: Vaniqa
Active Comparator: Diclofenac Na; Patients apply topical Diclofenac Na gel to their left forearm once daily on days 1-90.	Drug: Diclofenac Na gel; Given topically twice daily on days 1-90; Other Names: Solaraze
Experimental: Eflornithine HCL and Diclofenac Na; Eflornithine HCl ointment and Diclofenac Na gel applied twice and once daily, respectively on days 1-90.	Drug: Eflornithine HCL ointment; Given topically twice daily on days 1-90; Other Names: Vaniqa; Drug: Diclofenac Na gel; Given topically twice daily on days 1-90; Other Names: Solaraze

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months
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.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joanne M. Jeter, MD, University of Arizona

Publications and helpful links

General Publications

• Bozzo P, Saboda K, Einspahr JG, Ranger-Moore J, Farmer ER, Cockerell CJ, Elder DE, Bangert JL, Hart N, Kramer CB, Alberts DS. Reliability and validity of a histologic score as a marker for skin cancer chemoprevention studies. Anal Quant Cytol Histol. 2003 Oct;25(5):285-92.
• Jeter JM, Curiel-Lewandrowski C, Stratton SP, Myrdal PB, Warneke JA, Einspahr JG, Bartels HG, Yozwiak M, Bermudez Y, Hu C, Bartels P, Alberts DS. Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm. Cancer Prev Res (Phila). 2016 Feb;9(2):128-34. doi: 10.1158/1940-6207.CAPR-15-0232. Epub 2015 Dec 28.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: January 22, 2008
• First Submitted That Met QC Criteria: January 25, 2008
• First Posted (Estimate): January 28, 2008

Study Record Updates

• Last Update Posted (Actual): March 23, 2017
• Last Update Submitted That Met QC Criteria: February 2, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: skin cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Site; Neoplasms; Skin Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Ornithine Decarboxylase Inhibitors; Diclofenac; Eflornithine
• Other Study ID Numbers: 07-0032-04 (Other Identifier: UA IRB); P30CA023074 (U.S. NIH Grant/Contract); P01CA027502 (U.S. NIH Grant/Contract); UARIZ-BIO-06182 (Other Identifier: UA IRB no.)