Phase I Photodynamic Therapy (PDT) for Benign Dermal Neurofibromas (NF1)

Study Overview
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Brief Summary
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GENERAL OBJECTIVE The general objective is to assess the safety and efficacy of photodynamic therapy (PDT) in the treatment of neurofibromatosis 1 (NF1) tumors in the skin. SPECIFIC OBJECTIVE This is a light dose escalation pilot study to determine the safety and efficacy of PDT using 5-aminolevulinic acid (ALA) and 633 nm light in the treatment of benign dermal neurofibromas. Specifically, the primary goal of the current study is to determine the maximum tolerable light doses that can be administered to subjects undergoing topical photoillumination photodynamic therapy with standard application of Levulan Kerastick (ALA) for Topical Solution.

Detailed Description
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STUDY DESIGN This protocol is a Phase I light dose escalation pilot study to determine the safety and, secondarily, the efficacy of PDT using Levulan and 633 nm light in the treatment of benign dermal neurofibromas. This protocol represents the first two parts of a planned three part study including both pediatric and adult subjects. Part 1 will consist of studying the penetration and uptake of the PS in neurofibromas that are scheduled for excision. These tumors will be excised for therapeutic reasons unrelated to this study, and so this study will place no further burden on the subject other than a 3-24 hr incubation of the Levulan on the tumor prior to excision. The primary hypothesis to be tested is whether Levulan will accumulate, and be converted to PpIX, by the tumor tissue more than by the surrounding normal tissue. Secondary hypotheses are that tumors incubated with Levulan will show greater fluorescence than untreated tumors and tumors incubated with vehicle only (placebo application). As the Institutional Review Boards involved generally desire pilot data on adult populations first, we will with then proceed with the adult clinical trial portion of this protocol as part 2. Part 2 will use the optimum incubation time, if one has been identified in part 1, and add a dose escalation study of the amount of red light used to activate the Levulan. Part 3, with pediatric subjects, will commence at a future date, pending review of the initial adult study results.

Official Title
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Photodynamic Therapy for Benign Dermal Neurofibromas Using Levulan Kerastick For Topical Solution, Plus Illumination With Red Light

Conditions
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Neurofibromatoses

Intervention / Treatment
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* Drug: Part 1 Levulan injection
* Drug: Part 1 Levulan surface application
* Drug: Part 1 Levulan surface application twice
* Drug: Part 1 Levulan surface application twice with microneedling
* Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1
* Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2
* Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with NF1 will be selected for photodynamic therapy on the following criteria. Age: 18 years or older. NF1 will be diagnosed by American Academy of Neurology guidelines. Location of tumor: cutaneous, trunk or limbs only. Tumor type: superficial dermal neurofibromas, less than or equal to 4 mm deep. Growth confirmation: direct measurement for the dermal neurofibromas, ruler and photo-volumetric method. Informed consent of subject. Absence of any other malignancy. Only failures to meet criteria 1-6 due to the primary disease will be disqualifying Exclusion Criteria: Subjects will be excluded from participation in the study on the basis of the following: Life expectancy less than 1 year. Pregnancy. Inability to consent. Cutaneous photosensitivity to the wavelengths used to activate PDT. A diagnosis of porphyria. Allergy to aminolevulinic acid or any of the Topical Solution Vehicle components. Previous chemotherapy within 6 weeks of proposed PDT. Other concurrent tumor therapy. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Levulan injection<br>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 3 hr incubation, and by Levulan treated lesions after 3 or 24 hr incubation. | Drug: Part 1 Levulan injection<br>* Control or treatment lesions will be injected with Levulan vehicle only or active drug and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.<br>|
| Experimental: Part 1 Levulan painting<br>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 3 hr incubation, and by Levulan treated lesions and 3 or 24 hr incubation. | Drug: Part 1 Levulan surface application<br>* Control or treatment lesions will be painted with Levulan vehicle only or active drug, allowed to dry, and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.<br>|
| Experimental: Part 1 Levulan painted twice<br>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. | Drug: Part 1 Levulan surface application twice<br>* Control or treatment lesions will be painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 3 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.<br>|
| Experimental: Part 1 Levulan painted twice with microneedling<br>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. All lesions prepared with microneedling. | Drug: Part 1 Levulan surface application twice with microneedling<br>* Control or treatment lesions will be prepared with microneedling, painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 24 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.<br>|
| Experimental: Part 2 Dose level 1 50 J/cm^2<br>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements. | Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1<br>* 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 8 minutes to achieve a dose of 50 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.<br>|
| Experimental: Part 2 Dose level 2 100 J/cm^2<br>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements. | Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2<br>* 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 16 minutes to achieve a dose of 100 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.<br>|
| Experimental: Part 2 Dose level 3 200 J/cm^2<br>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3 - 200 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements. | Drug: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3<br>* 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 32 minutes to achieve a dose of 200 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX | The average fluorescence value for PpIX positive tumor areas in excised, sectioned tumors, as determined by fluorescence microscopy. PpIX signals were detected with excitation at 405 nm and emission with a 600 nm long pass filter. PpIX positive areas were determined to be those exhibiting fluorescence above background levels. | 24 hours | 
| Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light | MTD was determined by testing increasing doses up to 200 J/cm^2 on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of red light that did not cause a Dose-Limiting Toxicity (DLT) in > 33% of participants. DLT was defined as pain during irradiation requiring cessation of the light treatment, or any serious cutaneous adverse events. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Optimal Occlusion Time | An optimal occlusion time may be apparent from the results of the three time points. If no optimal occlusion time is seen, any occlusion time from 3-24 hours may be chosen for part 2. This secondary outcome measure is not critical to continuing the study, but may be useful in guiding treatment protocols | 24 hours | 
| Part 2: Efficacy - Lesion Area Growth Rate | Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects. | 12 weeks | 
| Part 2: Cosmetic Improvement | Potential cosmetic improvement using subject satisfaction scale. | 1 year | 
| Part 2: Pain Reduction | Potential pain reduction, as measured by standard visual analog 1-10 scale. | 1 year |