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Dermatologic Agents

Aminolevulinic Acid

Protoporphyrin IX

Photosensitizing Agents

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.

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.

5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation.

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.

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.

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.

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.

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.

Part 1 Levulan injection

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.

Part 1 Levulan surface application

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.

Part 1 Levulan surface application twice

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.

Part 1 Levulan surface application twice with microneedling

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.

Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1

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.

Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2

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.

Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3

Harry T Whelan, MD

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.

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.

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

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

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.

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.

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

Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects.

Potential cosmetic improvement using subject satisfaction scale.

Potential pain reduction, as measured by standard visual analog 1-10 scale.

Bleser Professor of Neurology

Tumors will be incubated with Levulan or vehicle under occlusion for 3 or 24 hrs. A minimum of three tumors per treatment or control group will be treated on the same subject. Tumors will then be excised in the normal manner. Tumors will be sectioned vertically and checked for PpIX using fluorescence microscopy.

Part 1 Levulan (5-aminolevulinic Acid) Uptake.

Experimental: Part 2 Dose Level 1 50 J/cm^2

Part 2 Dose Level 2 100 J/cm^2

Experimental: Part 1 Levulan Injection

Part 1 Levulan Painting

Part 1 Levulan Painted Twice

Part 1 Levulan Painted Twice With Microneedling

Part 2 Dose Level 1 50 J/cm^2

Part 2 Dose Level 3 200 J/cm^2

Total

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United States

Region of Enrollment

No subjects were enrolled into Part 2 Dose Level 3 as maximum tolerable dose had been established.

No participants in part 2 completed 1 year of follow-up visits, and are reported as lost to follow-up. This necessarily limits all outcome measurements for part 2 other than the maximum tolerable dose measurement.

Harry T. Whelan MD, Bleser Professor of Neurology

One-sample t-test comparing the absolute value to an alternate expected value of zero.

5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 24 hr incubation.

Part 1 Levulan Injection Control Lesions

5-aminolevulinic acid uptake by treated lesions after Levulan injection and 3 hr incubation.

Part 1 Levulan Injection Treated Lesions 3 Hours

5-aminolevulinic acid uptake by treated lesions after Levulan injection and 24 hr incubation.

Part 1 Levulan Injection Treated Lesions 24 Hours

5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 24 hr incubation.

Part 1 Levulan Paint Control Lesions

5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 3 hr incubation.

Part 1 Levulan Paint Treated Lesions 3 Hours

5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 24 hr incubation.

Part 1 Levulan Paint Treated Lesions 24 Hours

5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice and 3 hr incubation.

Part 1 Levulan Painted Twice Control Lesions

5-aminolevulinic acid uptake by treated lesions after Levulan surface application twice and 3 hr incubation.

Part 1 Levulan Painted Twice Treated Lesions

5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice, on lesions prepared with microneedling, and 24 hr incubation.

Part 1 Levulan Painted Twice Control Lesions With Microneedling

5-aminolevulinic acid uptake by treated lesions after Levulan surface application twice, on lesions prepared with microneedling, and 24 hr incubation.

Part 1 Levulan Painted Twice Treated Lesions With Microneedling

The first participant contributed three lesions to each of the first three groups. The second participant likewise for the second three groups. The next two participants contributed three lesions each to each of the next two groups. The next two participants contributed likewise for the last two groups. PpIX positive areas were detected only in the last group.

Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX

All participants who received at least 1 dose of 633 nm red light, either at 50 J/cm\^2, 100 J/cm\^2, or 200 J/cm\^2.

All Participants

Of the 14 enrolled in Part 2, 5 did not receive red light treatment per protocol. No subjects were enrolled in cohort 3 (200 J/cm\^2) due to marked pain in cohort 2. In the opinion of the clinical dermatologist, higher dose levels would likely not be tolerable, and it would be unethical to escalate the light dose further. It was decided that the MTD would be set at 100 J/cm\^2, and the highest dose level foregone.

Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light

The first participant contributed three lesions to each of the first three groups. The second participant contributed three lesions to each of the second three groups. Only the six groups in the first two arms are relevant to this outcome measure.

Part 1: Optimal Occlusion Time

Paired comparisons between treated and placebo lesions within subject.

Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm\^2 633 nm red light to Levulan vehicle (placebo) treated control 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.

Part 2 Dose Level 1 50 J/cm^2 Control

Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm\^2 633 nm red light to 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.

Part 2 Dose Level 1 50 J/cm^2 Treated

Only 5 participants from Part 2 dose level 1 of the study had lesion sizes monitored during follow-up visits.

Part 2: Efficacy - Lesion Area Growth Rate

Levulan (5-aminolevulinic acid) photodynamic therapy. 2-18 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 630 nm red light illumination. 630 nm light will be applied for varying periods of time in order to achieve a dose of 25, 50, or 100 J/cm2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.

Subjects will be seen at 24-48 hrs (48-72 hrs after Levulan application), and two weeks to one month after treatment at which times evaluation regarding dose toxicity will be made. Evaluations will include direct measurement of lesions, pain score, and cosmetic improvement (patient satisfaction).

At the 2 day follow up visit, tumors will be punch biopsied, samples preserved in paraffin or formalin, and evaluated for cell death using TUNEL assays, H \& E staining, or other methods.

Part 2 Levulan (5-aminolevulinic Acid) Photodynamic Therapy.

No cosmetic improvement data was collected.

Part 2: Cosmetic Improvement

Part 2: Pain Reduction

Average number of apoptotic cells per visual field among all TUNEL-evaluated lesion samples.

Only 5 participants from Part 2 dose level 1 of the study had biopsies performed and lesions analyzed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Photodynamic Therapy (PDT) for Benign Dermal Neurofibromas (NF1)	NCT01682811	Neurofibromatos...	Part 1 Levulan ... Part 1 Levulan ... Part 1 Levulan ... Part 1 Levulan ... Levulan (5-amin... Levulan (5-amin... Levulan (5-amin...	18 Years - 90 Years	Medical College of Wisconsin
Phase I Photodynamic Therapy (PDT) for Benign Dermal Neurofibromas (NF1)	NCT01682811	Neurofibromatos...	Part 1 Levulan ... Part 1 Levulan ... Part 1 Levulan ... Part 1 Levulan ... Levulan (5-amin... Levulan (5-amin... Levulan (5-amin...	18 Years - 90 Years	Medical College of Wisconsin

Spots Global Cancer Trial Database for part 1 levulan surface application