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

NCT01682811 | Completed Phase 1 Results

• 1 other identifier: PRO 14555
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Neurofibromatoses

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Part 1: Optimal Occlusion Time

  24 hours

• Part 2: Efficacy - Lesion Area Growth Rate

  12 weeks

• Part 2: Cosmetic Improvement

  1 year

• Part 2: Pain Reduction

  1 year

Study Arms (7)

Part 1 Levulan injection

EXPERIMENTAL

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

Part 1 Levulan painting

EXPERIMENTAL

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

Part 1 Levulan painted twice

EXPERIMENTAL

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

Part 1 Levulan painted twice with microneedling

EXPERIMENTAL

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

Part 2 Dose level 1 50 J/cm^2

EXPERIMENTAL

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

Part 2 Dose level 2 100 J/cm^2

EXPERIMENTAL

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

Part 2 Dose level 3 200 J/cm^2

EXPERIMENTAL

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

Interventions

Part 1 Levulan injection DRUG

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

Part 1 Levulan surface application DRUG

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 painting

Part 1 Levulan surface application twice DRUG

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 painted twice

Part 1 Levulan surface application twice with microneedling DRUG

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 painted twice with microneedling

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

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.

Part 2 Dose level 1 50 J/cm^2

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

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.

Part 2 Dose level 2 100 J/cm^2

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

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.

Part 2 Dose level 3 200 J/cm^2

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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. -

Sponsors & Collaborators

• Harry T Whelan, MD: lead

Study Sites (1)

The Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Quirk B, Olasz E, Kumar S, Basel D, Whelan H. Photodynamic Therapy for Benign Cutaneous Neurofibromas Using Aminolevulinic Acid Topical Application and 633 nm Red Light Illumination. Photobiomodul Photomed Laser Surg. 2021 Jun;39(6):411-417. doi: 10.1089/photob.2020.4957. Epub 2021 Jan 20.

  PMID: 33470897 DERIVED

MeSH Terms

Conditions

Neurofibromatoses

Interventions

Percutaneous Collagen Induction; Aminolevulinic Acid

Condition Hierarchy (Ancestors)

Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Complementary Therapies; Therapeutics; Physical Therapy Modalities; Punctures; Rehabilitation; Levulinic Acids; Keto Acids; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Limitations and Caveats

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.

Results Point of Contact

• Title: Harry T. Whelan MD, Bleser Professor of Neurology
• Organization: Medical College of Wisconsin

hwhelan@mcw.edu

414-266-7544

Study Officials

• Harry T Whelan, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Bleser Professor of Neurology

Study Record Dates

• First Submitted: September 5, 2012
• First Posted: September 11, 2012
• Study Start: March 12, 2012
• Primary Completion: October 23, 2015
• Study Completion: July 7, 2016
• Last Updated: June 18, 2021
• Results First Posted: June 18, 2021

Record last verified: 2021-06

Locations

US (1)