Neurofibromatoses
Conditions
Brief summary
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
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.
Interventions
DRUGPart 1 Levulan injection
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.
DRUGPart 1 Levulan surface application
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.
DRUGPart 1 Levulan surface application twice
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.
DRUGPart 1 Levulan surface application twice with microneedling
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.
DRUGLevulan (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 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.
DRUGLevulan (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 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.
DRUGLevulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3
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.
Sponsors
Harry T Whelan, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Subjects with NF1 will be selected for photodynamic therapy on the following criteria. 1. Age: 18 years or older. 2. NF1 will be diagnosed by American Academy of Neurology guidelines. 3. Location of tumor: cutaneous, trunk or limbs only. 4. Tumor type: superficial dermal neurofibromas, less than or equal to 4 mm deep. 5. Growth confirmation: direct measurement for the dermal neurofibromas, ruler and photo-volumetric method. 6. Informed consent of subject. 7. Absence of any other malignancy. 8. 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: 1. Life expectancy less than 1 year. 2. Pregnancy. 3. Inability to consent. 4. Cutaneous photosensitivity to the wavelengths used to activate PDT. 5. A diagnosis of porphyria. 6. Allergy to aminolevulinic acid or any of the Topical Solution Vehicle components. 7. Previous chemotherapy within 6 weeks of proposed PDT. 8. Other concurrent tumor therapy. -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX | 24 hours | 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. |
| Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light | 48 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Optimal Occlusion Time | 24 hours | 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 |
| Part 2: Efficacy - Lesion Area Growth Rate | 12 weeks | Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects. |
| Part 2: Cosmetic Improvement | 1 year | Potential cosmetic improvement using subject satisfaction scale. |
| Part 2: Pain Reduction | 1 year | Potential pain reduction, as measured by standard visual analog 1-10 scale. |
Countries
United States
Participant flow
Recruitment details
A prospective, controlled, nonrandomized phase I clinical trial was conducted between March 2012 and July 2016. This study included adult patients from Froedtert Hospital in Milwaukee, Wisconsin. NF1 patients were recruited through referral by their physician.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Part 1 Levulan Injection 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. | 1 |
| Experimental: Part 1 Levulan Injection 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. | 9 |
| Part 1 Levulan Painting 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. | 1 |
| Part 1 Levulan Painting 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. | 9 |
| Part 1 Levulan Painted Twice 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. | 2 |
| Part 1 Levulan Painted Twice 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. | 12 |
| Part 1 Levulan Painted Twice With Microneedling 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. | 2 |
| Part 1 Levulan Painted Twice With Microneedling 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. | 12 |
| Part 2 Dose Level 1 50 J/cm^2 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. | 11 |
| Part 2 Dose Level 1 50 J/cm^2 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. | 60 |
| Part 2 Dose Level 2 100 J/cm^2 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. | 3 |
| Part 2 Dose Level 2 100 J/cm^2 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. | 18 |
| Part 2 Dose Level 3 200 J/cm^2 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. | 0 |
| Part 2 Dose Level 3 200 J/cm^2 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. | 0 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 2 Dose Level 1 | Lost to Follow-up | 0 | 0 | 0 | 0 | 6 | 0 | 0 |
| Part 2 Dose Level 1 | Protocol Violation | 0 | 0 | 0 | 0 | 4 | 0 | 0 |
| Part 2 Dose Level 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2 Dose Level 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Part 2 Dose Level 2 100 J/cm^2 | Total | 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 |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 7 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 13 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 7 Participants | 0 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — | — | — | — | — | — |
| Region of Enrollment United States | 3 participants | 20 participants | 1 participants | 1 participants | 2 participants | 2 participants | 11 participants | — |
| Sex: Female, Male Female | 1 Participants | 13 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 8 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 11 | 0 / 3 |
| other Total, other adverse events | 0 / 6 | 1 / 11 | 0 / 3 |
| serious Total, serious adverse events | 0 / 6 | 0 / 11 | 0 / 3 |
Outcome results
Primary
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.
Time frame: 24 hours
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Levulan Painted Twice Treated Lesions With Microneedling | Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX | 304 Densitometry units/micrometer squared | Standard Deviation 94 |
Comparison: One-sample t-test comparing the absolute value to an alternate expected value of zero.p-value: 0.0001t-test, 1 sided
Primary
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.
Time frame: 48 hours
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Levulan Injection Control Lesions | Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light | 100 joules/cm squared |
Secondary
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
Time frame: 24 hours
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Levulan Injection Control Lesions | Part 1: Optimal Occlusion Time | NA hours |
| Part 1 Levulan Injection Treated Lesions 3 Hours | Part 1: Optimal Occlusion Time | NA hours |
| Part 1 Levulan Injection Treated Lesions 24 Hours | Part 1: Optimal Occlusion Time | NA hours |
| Part 1 Levulan Paint Control Lesions | Part 1: Optimal Occlusion Time | NA hours |
| Part 1 Levulan Paint Treated Lesions 3 Hours | Part 1: Optimal Occlusion Time | NA hours |
| Part 1 Levulan Paint Treated Lesions 24 Hours | Part 1: Optimal Occlusion Time | NA hours |
Secondary
Part 2: Cosmetic Improvement
Potential cosmetic improvement using subject satisfaction scale.
Time frame: 1 year
Population: No cosmetic improvement data was collected.
Secondary
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.
Time frame: 12 weeks
Population: Only 5 participants from Part 2 dose level 1 of the study had lesion sizes monitored during follow-up visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Levulan Injection Control Lesions | Part 2: Efficacy - Lesion Area Growth Rate | 0.212 millimeter squared/day post-treatment | Standard Deviation 0.364 |
| Part 1 Levulan Injection Treated Lesions 3 Hours | Part 2: Efficacy - Lesion Area Growth Rate | 0.081 millimeter squared/day post-treatment | Standard Deviation 0.176 |
Comparison: Paired comparisons between treated and placebo lesions within subject.p-value: 0.24t-test, 2 sided
Secondary
Part 2: Pain Reduction
Potential pain reduction, as measured by standard visual analog 1-10 scale.
Time frame: 1 year
Population: No pain reduction data was collected.
Post Hoc
TUNEL Assay.
Average number of apoptotic cells per visual field among all TUNEL-evaluated lesion samples.
Time frame: 48 hours
Population: Only 5 participants from Part 2 dose level 1 of the study had biopsies performed and lesions analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Levulan Injection Control Lesions | TUNEL Assay. | 42.5 apoptotic cells/visual field | Standard Deviation 19.9 |
| Part 1 Levulan Injection Treated Lesions 3 Hours | TUNEL Assay. | 1.1 apoptotic cells/visual field | Standard Deviation 1.4 |
p-value: 0.002t-test, 2 sided