131-I-MIBG Therapy for Refractory Neuroblastoma, Expanded Access Protocol

131I-MIBG is experimental, but has been used in more than 100 children in the United States by itself to treat relapsed neuroblastoma. A recent study using increasing doses of 131I-MIBG in both children and adults with relapsed neuroblastoma or metastatic pheochromocytoma/ganglioma showed anti-cancer effects in some of these patients. The main side effect of this treatment was a decrease in the number of normal blood-forming cells (called stem cells) in the bone marrow, but a dose of 12 mCi/kg did not cause permanent damage to the bone marrow in a small number of patients.

There are certain tests or procedures that will need to be done to confirm that the subject is eligible for this therapy. These include lab work, physical exam and MIBG scan. A CT scan, an MRI, a bone scan, bone marrow aspirate and biopsy and urine tests will be done to evaluate your disease status when clinically indicated. Your doctor will determine which tests are required.

Subjects will need to have an intravenous catheter (tube) placed in a vein before beginning study treatment. An existing central venous catheter can be used to administer the medicine.

Because subjects' urine will be radioactive, a urinary catheter may be inserted to ensure drainage of the urine, which will be radioactive. The catheter will be removed 3-5 days following the treatment. General anesthesia or sedation is typically given for the procedure of inserting the catheter.

Subjects will be treated in a specially prepared room in the CHOP Pediatric Oncology Unit. Upon admission, the nursing staff will instruct caregivers on the care of the subject following the MIBG infusion. Because of the frequent exposure of the nursing staff to radiation and the high level of radiation surrounding the subject during therapy, the nurses' contact will be limited to complex medical care, so that they are available for subjects in the event of an emergency. Adult family members will be expected to be present at all times during the hospitalization to:

• Assist with hygiene
• Give oral medications
• Offer and empty bedpans
• Assist with meals
• Change diapers (if used)
• Change clothing and bed linens if soiled
• Entertain or distract individuals who become upset or restless due to the isolation or procedures.
• Record Dosimeter readings.

Isolation: For 2-5 days subjects will be placed in a single room with a bed surrounded by lead shielding to prevent exposure of visitors and hospital personnel to radioactivity. Family members may visit in the room, but must wear a radiation badge to measure exposure. A single family member can sleep in the room, but no one is allowed to go behind the shields or sleep in the bed with the child.

Subjects will receive fluids through the central venous catheter. The fluids will begin at least four hours before and continue at least 72 hours after the 131I-MIBG treatment begins.

Subjects will take a medicine by mouth, potassium iodide, to prevent thyroid damage from the radioactive iodine contained in the 131I-MIBG. This medication will be taken on the day of the treatment and will continue for a total of 6 weeks.

The 131I-MIBG will be given through an intravenous catheter over 1-2 hours.

During the administration of the drug, subject's blood pressure and heart rate will be checked frequently.

Before and at regular intervals after treatment, subjects will have routine blood tests to check his/her blood counts, hormone, liver and kidney functions. Blood will be checked frequently for the first 1-6 weeks, and 6 weeks after the treatment. Approximately 1 teaspoon of blood will be drawn each time during the first 6 weeks to perform the tests listed above.

An MIBG scan will be performed to see where the drug is concentrating in the body following treatment. No injection of a radioactive marker will be required and this is usually done on the day for discharge. It is identical to the pretherapy MIBG scan except for not needing MIBG injection and it is usually shorter (15-30 minutes).

Six to eight weeks after treatment, an MIBG and other scans will be done to evaluate the response of the tumor to the treatment.

If the subject's tumor is responding or stable 6-7 weeks after each treatment, they may be eligible for a second and third course of treatment, as long as their white blood counts have recovered from the treatment and the patient has stem cells available if needed. If another MIBG treatment is given, it will be at the same dose as the first treatment, unless it is thought to be necessary for safety reasons (based on toxicity information from the first infusion) to decrease the dose.

If the subject's blood counts decrease following the therapy, treatment with Filgrastim (G-CSF) or Neulasta may be required. G-CSF/neulasta is a medicine that helps increase the white blood cells. This is given by a subcutaneous (under the skin) injection (like an insulin shot). GCSF is given daily and Neulasta is given every 14 days instead of GCSF. Neulasta works like GCSF to help increase the white blood counts but lasts longer in your child's body. This medicine will start if the absolute neutrophil count (ANC), a measure of the infection fighting cells, goes below 500 and will continue until recovery, generally above 5000.

Vorinostat may be given at the discretion of the PI and treating physician as a clinical procedure. This will be administered for clinical purposes, regardless of study participation. Patients will receive 180 mg/m2/dose (maximum dose 400 mg) as in the recently completed NANT study once daily by mouth, NG, or G-tube on days 0 to +13 (14 total doses). Vorinostat will be given for 14 days continuously. Vorinostat should be taken with food or within 30 minutes after a meal. The dose should be taken in the morning whenever possible. On day 1 of therapy, vorinostat should be taken 1 hour prior to the start of the 131I-MIBG infusion.