Actinic Keratosis, Organ or Tissue Transplant; Complications
Conditions
Keywords
Actinic Keratosis, Photodynamic Therapy
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.
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.
Interventions
DRUG5-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.
Sponsors
National Cancer Institute (NCI)
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Actinic Keratosis (AK) Clearance | AK counts, over a 12-month period | Rate of AK clearance (Analyzed by linear mixed-effect model) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Solid Organ Transplant With AKs 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. | 4 |
| 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. | 14 |
| Total | 18 |
Baseline characteristics
| Characteristic | Solid Organ Transplant With AKs | Actinic Keratoses | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 10 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 14 Participants | 18 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 11 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 0 / 14 |
| serious Total, serious adverse events | 1 / 4 | 0 / 14 |
Outcome results
Primary
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).
Time frame: Day 7 of the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Transplant With AKs; 5FU + PDT | Accumulation of Porphyrin (PpIX) | 101.8 Change in PpIX signal (arbitrary units) |
| Transplant With AKs; PDT Only | Accumulation of Porphyrin (PpIX) | 48.0 Change in PpIX signal (arbitrary units) |
| Normals With AKs; 5FU + PDT | Accumulation of Porphyrin (PpIX) | 84.3 Change in PpIX signal (arbitrary units) |
| Normals With AKs; PDT Only | Accumulation of Porphyrin (PpIX) | 38.4 Change in PpIX signal (arbitrary units) |
p-value: <0.007t-test, 2 sided
p-value: 0.08t-test, 2 sided
Secondary
Actinic Keratosis (AK) Clearance
Rate of AK clearance (Analyzed by linear mixed-effect model)
Time frame: AK counts, over a 12-month period
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Transplant With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | 9 mos (see ClinCaRes2018)) | 0 CR (% reduction) |
| Transplant With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | 12 mos (see ClinCaRes 2018) | 0 CR (% reduction) |
| Transplant With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | At 3 months post-PDT | 76.7 CR (% reduction) |
| Transplant With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | At 6 months post-PDT | 58.4 CR (% reduction) |
| Transplant With AKs; PDT Only | Actinic Keratosis (AK) Clearance | At 3 months post-PDT | 34.6 CR (% reduction) |
| Transplant With AKs; PDT Only | Actinic Keratosis (AK) Clearance | At 6 months post-PDT | 23.8 CR (% reduction) |
| Transplant With AKs; PDT Only | Actinic Keratosis (AK) Clearance | 12 mos (see ClinCaRes 2018) | 0 CR (% reduction) |
| Transplant With AKs; PDT Only | Actinic Keratosis (AK) Clearance | 9 mos (see ClinCaRes2018)) | 0 CR (% reduction) |
| Normals With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | At 3 months post-PDT | 73.4 CR (% reduction) |
| Normals With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | 9 mos (see ClinCaRes2018)) | 0 CR (% reduction) |
| Normals With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | At 6 months post-PDT | 69.0 CR (% reduction) |
| Normals With AKs; 5FU + PDT | Actinic Keratosis (AK) Clearance | 12 mos (see ClinCaRes 2018) | 0 CR (% reduction) |
| Normals With AKs; PDT Only | Actinic Keratosis (AK) Clearance | 9 mos (see ClinCaRes2018)) | 0 CR (% reduction) |
| Normals With AKs; PDT Only | Actinic Keratosis (AK) Clearance | At 3 months post-PDT | 49.5 CR (% reduction) |
| Normals With AKs; PDT Only | Actinic Keratosis (AK) Clearance | 12 mos (see ClinCaRes 2018) | 0 CR (% reduction) |
| Normals With AKs; PDT Only | Actinic Keratosis (AK) Clearance | At 6 months post-PDT | 43.1 CR (% reduction) |
p-value: <0.05t-test, 2 sided
p-value: <0.001t-test, 2 sided
Post Hoc
New AK Lesion Development
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant With AKs; 5FU + PDT | New AK Lesion Development | 8.1 months | Standard Deviation 2.8 |
| Transplant With AKs; PDT Only | New AK Lesion Development | 8.5 months | Standard Deviation 2.4 |