Phase I Clinical Study of the Safety of Photodynamic Therapy (PDT) Using LS11 in Children With Plexiform Neurofibromas (PDT)

Current treatment options for PN are limited. The only effective therapy for PN is complete surgical resection. Incompletely resected lesions have a high incidence of recurrence, often resulting in the necessity of several surgeries over a patient's lifetime. Development of non-surgical treatments for PN is a high priority. To date, other therapeutic modalities, including radiotherapy and chemotherapy, have not shown efficacy in PN, although it is arguable that these modalities have not been sufficiently studied. Newer approaches, including anti-angiogenesis agents, farnesyl transferase inhibitors, and inhibitors of growth factor pathways are in development and are being studied, but are clearly not proven therapies.

Investigational Agent LS11, talaporfin sodium, was specifically developed as a photosensitizing agent for use in photodynamic therapy. The light activation of LS11 leads to the formation of singlet oxygen causing damage to the vascular endothelial cells leading to vascular thrombosis and occlusion.

Phase I and II studies were conducted in the US and Japan using LS11. PDT with LS11 was generally well tolerated in these studies and there were no serious adverse events noted.

PDT is a novel treatment modality in which a systemically administered photosensitizer (LS11 in our proposal) is activated locally by illuminating the diseased tissue with light of a specific wavelength. Light activation of LS11 leads to the formation of reactive oxygen species that cause damage to the vascular endothelial cells leading to vascular thrombosis and occlusion and subsequently death of tumor cells.

Light Source Placement: Ultrasound may be used to monitor the percutaneous implantation of the Light Source. However, the position of the implanted Light Source must be verified by computed tomography (CT).

• Use a RITA introducer that has a trochar.
• Make a small incision in the skin.
• Insert the introducer into the tumor and advance to the desired position in the target tissue (using ultrasound or CT to verify placement).
• Remove the trochar.
• Insert the Light Source catheter to the end of the sheath. (Avoid mechanical damage to the device, such as twisting, kinking, or exerting force during insertion).
• Pull the sheath back at least 4 centimeters (cm) (the Light Source has to remain in position and not be pulled back with the sheath).
• Verify the Light Source tip location by CT. Reposition if necessary.
• The sheath may be removed completely, after verifying Light Source tip location, at the physician's discretion
• Record distance to lesion surface and to vital structures of the implanted light source.
• Secure the Light Source

LS11 Administration:

• Since compatibility between LS11 and other drugs is not established, LS11 should not be mixed with or physically added to other drugs.
• Every effort should be made to avoid extravasation of LS11 in the surrounding tissue. The extravasated drug may pose prolonged photosensitivity risk to the tissue near the injection site.
• To avoid extravasation, establish an intravenous (IV) line and ensure that there is a free flow of saline or dextrose and water. If a heparin lock is used, flush thoroughly with saline.
• LS11 should be slowly (over 3-5 minutes) administered intravenously as a single dose of 30 mg/m2 or 40 mg/m2.
• Following the injection the line should be flushed with at least 10 cc of saline or dextrose and water.
• In case of extravasation, the site should be thoroughly rinsed with saline or water and carefully bandaged to protect the area from room- and sun-light. The photosensitivity at the extravasated site will last longer than general cutaneous photosensitivity.
• Record the administration start time and end time.

Physical exam, blood tests, electrocardiogram (ECG) and magnetic resonance imaging (MRI) will be performed prior to starting on study and regularly after the treatment per protocol.

Light Exposure Precautions Following PDT-Instructions for Patients: Patients will be sensitive to light and must observe precautions to reduce exposure of skin and eyes to direct sunlight and bright indoor lighting for up to 14 days. The sensitivity to light is due to residual drug that will be present in all parts of the skin and eyes. To minimize skin reactions due to light exposure after LS11 administration, precautions should be taken as detailed in the protocol.