Combination Therapy With 5-Fluorouracil and Photodynamic Therapy in Post-transplant Premalignant Skin Disease

Study Overview
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Brief Summary
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This randomized, intra-patient comparative study is designed to investigate the combination regimen of 5-fluorouracil cream (5FU) and Photodynamic Therapy (PDT), versus PDT alone, for its ability to generate significantly elevated levels of the target photosensitizer, protoporphyrin IX (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.

Detailed Description
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This clinical trial will test a new combination of 5-fluorouracil cream (5FU) and methylaminolevulinate 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). We plan to enroll 20 organ transplant recipients and 20 normal patients, with AKs on face, scalp, ears, forearms or back of the hand 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.

Official Title
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Combination Therapy With 5-Fluorouracil and Photodynamic Therapy for the Treatment of Post-transplant Premalignant Skin Disease

Conditions
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Actinic Keratosis, Organ or Tissue Transplant; Complications

Intervention / Treatment
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* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid Organ Transplant with AKs<br>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<br>* 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.<br>* Other names: 5-FU;|
| Active Comparator: Actinic Keratoses<br>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<br>* 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.<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accumulation of Porphyrin (PpIX) | 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). | Day 7 of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actinic Keratosis (AK) Clearance | Rate of AK clearance (Analyzed by linear mixed-effect model) | AK counts, over a 12-month period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Photodynamic Therapy, Actinic Keratosis