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

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01525329
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 18
• Location: 1
• Arms: 2
• Duration (Months): 63
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

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 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 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: Sep 1, 2011
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

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

Primary Outcome Measures

1. Accumulation of Porphyrin (PpIX) [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. Actinic Keratosis (AK) Clearance [AK counts, over a 12-month period]

   Rate of AK clearance (Analyzed by linear mixed-effect model)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Edward Maytin, MD, PhD, Section Head, Molecular Dermatology; Chairman, Dermatology Research Committee, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01525329
• Other Study ID Numbers: 09-1050; 1R21CA156227-01A1
• First Posted: Feb 2, 2012
• Last Update Posted: Mar 15, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Edward Maytin, MD, PhD, Section Head, Molecular Dermatology; Chairman, Dermatology Research Committee, The Cleveland Clinic: Actinic Keratosis; Photodynamic Therapy
• Additional relevant MeSH terms: Keratosis, Actinic; Precancerous Conditions; Keratosis; Skin Diseases; Fluorouracil

Study Results

Participant Flow

Arm/Group Title	Solid Organ Transplant With AKs	Actinic Keratoses
Arm/Group Description	Patients who underwent kidney or liver transplant within 2 years, and with at least 4 premalignant skin lesions on face, ears, scalp, forearms or dorsal hands. Patients will serve as their own control; one side of the body will be randomized to 5-FU plus PDT, and the other to PDT alone. All patients will receive one cream, 5-Fluorouracil (5FU), and will apply it to the AKs on either the right or left side of the face/scalp (per randomization scheme), once daily for 6 d prior to PDT. The ability of AKs to produce PpIX will be measured at baseline by applying methyl-aminolevulinate (Metvixia® topical cream) to the selected AKs using a fluorescence dosimeter. Prior to Metvixia, and again 3 hours after application, surface measurements of PpIX fluorescence will be taken. Then the two largest lesions (one on the left, one on the right) will be biopsied under local anesthesia, followed by red light PDT (lasting ~8 minutes). Biopsy sites will be shielded from light with a spot bandage.	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. All patients will receive one cream, 5-Fluorouracil (5FU), and will apply it to the AKs on either the right or left side of the face/scalp (per randomization scheme), once daily for 6 d prior to PDT. The ability of AKs to produce PpIX will be measured at baseline by applying methyl-aminolevulinate (Metvixia® topical cream) to the selected AKs using a fluorescence dosimeter. Prior to Metvixia, and again 3 hours after application, surface measurements of PpIX fluorescence will be taken. Then the two largest lesions (one on the left, one on the right) will be biopsied under local anesthesia, followed by red light PDT (lasting ~8 minutes). Biopsy sites will be shielded from light with a spot bandage.
Period Title: Overall Study
STARTED	4	14
COMPLETED	4	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Solid Organ Transplant With AKs	Actinic Keratoses	Total
Arm/Group Description	Patients who underwent kidney or liver transplant within 2 years, and with at least 4 premalignant skin lesions on face, ears, scalp, forearms or dorsal hands. Patients will serve as their own control; one side of the body will be randomized to 5-FU plus PDT, and the other to PDT alone.	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.	Total of all reporting groups
Overall Participants	4	14	18
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	4 28.6%	8 44.4%
>=65 years	0 0%	10 71.4%	10 55.6%
Sex: Female, Male (Count of Participants)
Female	1 25%	3 21.4%	4 22.2%
Male	3 75%	11 78.6%	14 77.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	4 100%	14 100%	18 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Accumulation of Porphyrin (PpIX)
Description	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).
Time Frame	Day 7 of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transplant With AKs; 5FU + PDT	Transplant With AKs; PDT Only	Normals With AKs; 5FU + PDT	Normals With AKs; PDT Only
Arm/Group Description	Patient with solid organ transplant: half of body receiving combination therapy	Patient with solid organ transplant: half of body receiving PDT alone	Patient without any organ transplant: half of body receiving combination therapy	Patient without any organ transplant: half of body receiving PDT alone
Measure Participants	4	4	14	14
Mean (95% Confidence Interval) [Change in PpIX signal (arbitrary units)]	101.8	48.0	84.3	38.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Transplant With AKs; 5FU + PDT, Transplant With AKs; PDT Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.007
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Normals With AKs; 5FU + PDT, Normals With AKs; PDT Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transplant With AKs; 5FU + PDT	Transplant With AKs; PDT Only	Normals With AKs; 5FU + PDT	Normals With AKs; PDT Only
Arm/Group Description	Patient with solid organ transplant: half of body receiving combination therapy	Patient with solid organ transplant: half of body receiving PDT alone	Patient without any organ transplant: half of body receiving combination therapy	Patient without any organ transplant: half of body receiving PDT alone
Measure Participants	4	4	14	14
At 3 months post-PDT	76.7	34.6	73.4	49.5
At 6 months post-PDT	58.4	23.8	69.0	43.1
9 mos (see ClinCaRes2018))	0	0	0	0
12 mos (see ClinCaRes 2018)	0	0	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Transplant With AKs; 5FU + PDT, Transplant With AKs; PDT Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Normals With AKs; 5FU + PDT, Normals With AKs; PDT Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

3. Post-Hoc Outcome

Title	New AK Lesion Development
Description	The time (in months) following PDT treatment at which AK lesion counts first began to increase again. (Note: The nadir in AK lesion counts is reached at about 3 months in almost all patients).
Time Frame	12 months post-PDT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PDT Only	5-FU Followed by PDT
Arm/Group Description	Patients who did not receive 5-FU prior to PDT	Patients who received a week of topical 5-FU pretreatment prior to PDT
Measure Participants	17	17
Mean (Standard Deviation) [months]	8.1 (2.8)	8.5 (2.4)

Adverse Events

Time Frame	2 years
Arm/Group Title	Solid Organ Transplant With AKs		Actinic Keratoses
Arm/Group Description	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 with at least 4 actinic keratoses on the face, ears, scalp, forearms and/or dorsal hands.
All Cause Mortality
	Solid Organ Transplant With AKs		Actinic Keratoses
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Solid Organ Transplant With AKs		Actinic Keratoses
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		0/14 (0%)
Vascular disorders
Stroke	1/4 (25%)	1	0/14 (0%)	0
Other (Not Including Serious) Adverse Events
	Solid Organ Transplant With AKs		Actinic Keratoses
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.