Combination Therapy With 5-FU and PDT for the Treatment of Post-transplant Premalignant Skin Disease

Study Description

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Brief Summary:

This randomized, intra-patient comparative study is designed to investigate the combination regimen of 5-FU and PDT, versus PDT alone, for its ability to generate significantly elevated levels of the target photosensitizer, PpIX, in lesions of actinic keratoses (AKs) and to more effectively treat and prevent recurrence of AKs. The target population comprises patients with solid organ transplants (renal, hepatic), as well as normal (immunocompetent) subjects to control for possible influences of immunosuppression.

Condition or disease	Intervention/treatment	Phase
Actinic Keratosis; Organ or Tissue Transplant; Complications	Drug: 5-Fluorouracil	Phase 3

Detailed Description:

This clinical trial will test a new combination of 5-fluorouracil cream (5FU) and methylaminolevate photodynamic therapy (MAL-PDT), versus MAL-PDT alone, as treatment for actinic keratoses (AKs) in immunosuppressed organ transplant recipients (OTRs) and an immunocompetent control group. Objectives: 1) Determine whether topical pretreatment with 5-FU selectively increases the amount of photosensitizer (PpIX) produced within AK lesions, relative to non-pretreated lesions. 2) Determine whether the combination treatment improves lesion resolution and reduces the incidence of new AKs. 3) Determine whether biomarkers in tissue and blood are predictive of patient responsiveness to 5FU (PpIX induction, new lesion incidence, and clinical toxicity).

20 organ transplant recipients and 20 normal patients, with AKs on face, scalp, ears, forearms or back of the hand are enrolled through Dermatology and Transplant Clinic at Cleveland Clinic. Women of childbearing age must use contraception and have a negative pregnancy test.

Study participants will apply 5FU daily for 6 days; MAL/PDT is administered on 7th day. PpIX will be measured in lesions using a noninvasive dosimeter. Biopsies will be taken from selected lesions, and AKs will be photographed. Participants will be asked to complete a questionnaire to document adverse events. Patients are evaluated at day 14, and months 3, 6, 9, 12, to document AK clearance and new lesion appearance.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	19 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Combination Therapy With 5-Fluorouracil and Photodynamic Therapy for the Treatment of Post-transplant Premalignant Skin Disease
Study Start Date :	September 2011
Actual Primary Completion Date :	November 2016
Actual Study Completion Date :	December 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Solid Organ Transplant with AKs; Patients who have undergone kidney or liver transplant within 2 years and have at least 4 premalignant skin lesions on the face, ears, scalp, forearms and/or dorsal hands. Patients will serve as their own control, and one side of the body will be randomized to either 5-FU plus PDT, and the other will receive PDT alone.	Drug: 5-Fluorouracil; All patients will receive one cream, 5-Fluorouracil, and will be instructed to apply the cream according to the randomization schema to AKs on either the right or left side of the face/scalp once a day for 6 days prior to PDT. A baseline measurement of the tumor's ability to produce PpIX will be done by applying methyl-aminolevulinic acid (Metvixia® topical cream) to the selected AKs and using the Aurora© dosimeter. Prior to Metvixia, and again 3 hours after application, surface measurements of the PpIX fluorescence will be taken. Then, the two largest precancer lesions (one on the left side, one on the right side) will be biopsied under local anesthesia, followed by red light PDT (lasting ~8 minutes). The biopsy sites will be shielded from the light with a circular spot bandage.; Other Names: Fluorouracil Cream, USP 5%; 5-FU
Active Comparator: Actinic Keratoses; Patients with at least 4 actinic keratoses on the face, ears, scalp, forearms and/or dorsal hands. Patients will serve as their own control, and one side of the body will be randomized to either 5-FU plus PDT, and the other will receive PDT alone.	Drug: 5-Fluorouracil; All patients will receive one cream, 5-Fluorouracil, and will be instructed to apply the cream according to the randomization schema to AKs on either the right or left side of the face/scalp once a day for 6 days prior to PDT. A baseline measurement of the tumor's ability to produce PpIX will be done by applying methyl-aminolevulinic acid (Metvixia® topical cream) to the selected AKs and using the Aurora© dosimeter. Prior to Metvixia, and again 3 hours after application, surface measurements of the PpIX fluorescence will be taken. Then, the two largest precancer lesions (one on the left side, one on the right side) will be biopsied under local anesthesia, followed by red light PDT (lasting ~8 minutes). The biopsy sites will be shielded from the light with a circular spot bandage.; Other Names: Fluorouracil Cream, USP 5%; 5-FU

Outcome Measures

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Primary Outcome Measures :

1. Accumulation of PpIX [ Time Frame: Day 7 of the study ]

   The primary endpoint of this study will be the accumulation of PpIX at 3 h after MAL application (measured noninvasively, in each treated region).

   (Region refers to the half-face or half-scalp area treated with PDT monotherapy, or the contralateral area treated with the 5-FU/PDT combination regimen).

Secondary Outcome Measures :

1. AK clearance [ Time Frame: At Day 14 and at 3 months post-treatment ]
   1) Rate of AK clearance at Day 14 (at the time of suture removal) and at 3 months
2. Development of new AKs [ Time Frame: At 3, 6, 9, and 12 months post-treatment ]
   Rate of development of new AK at months 3, 6 9, and 12

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• At least 18 years of age
• At least four (4) actinic keratoses, located on face, ears, scalp, forearms and/or dorsal hands. - Patients in the solid organ transplant arm of the study must have had either a kidney or liver transplant, and the transplantation surgery must have occurred at least 2 years prior to enrollment.

Exclusion Criteria:

• Pregnant or nursing
• Currently participating in another clinical trial
• Using any topical treatment for their actinic keratoses
• Currently being treated for other cancers with medical or radiation therapy
• Patients with a known hypersensitivity to 5-aminolevulinic acid, 5-fluorouracil or any component of the study material
• Patients with a history of a photosensitivity disease, including porphyria cutanea tarda

Contacts and Locations

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Locations

United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

The Cleveland Clinic

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Edward Maytin, MD, PhD	The Cleveland Clinic

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Maytin EV, Anand S, Riha M, Lohser S, Tellez A, Ishak R, Karpinski L, Sot J, Hu B, Denisyuk A, Davis SC, Kyei A, Vidimos A. 5-Fluorouracil enhances Protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses: A mechanism-based clinical trial. Clin Cancer Res. 2018 Mar 28. pii: clincanres.2020.2017. doi: 10.1158/1078-0432.CCR-17-2020. [Epub ahead of print]

Responsible Party:	Edward Maytin, Section Head, Molecular Dermatology; Chairman, Dermatology Research Committee, The Cleveland Clinic
ClinicalTrials.gov Identifier:	NCT01525329 History of Changes
Other Study ID Numbers:	09-1050; 1R21CA156227-01A1 ( U.S. NIH Grant/Contract )
First Posted:	February 2, 2012
Last Update Posted:	January 4, 2017
Last Verified:	January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	there is no plan to share individual participant data with other researchers.

Keywords provided by Edward Maytin, The Cleveland Clinic:

Actinic Keratosis; Photodynamic Therapy

Additional relevant MeSH terms:

Keratosis; Keratosis, Actinic; Skin Diseases; Precancerous Conditions; Neoplasms; Fluorouracil; Antimetabolites	Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs