131-I-MIBG Therapy for Refractory Neuroblastoma and Metastatic Paraganglioma/Pheochromocytoma

131I-MIBG is experimental, but has been used in more than 100 children in the United States
by itself to treat relapsed neuroblastoma and metastatic pheochromocytoma/ganglioma. 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 750 and will continue until it rises above 5000.

Inclusion Criteria:

- Refractory or relapsed neuroblastoma OR malignant Paraganglioma or Pheochromocytoma

- Age greater than 1 year and able to cooperate with radiation safety restrictions
during therapy period.

- Performance Level: Patients must have a Karnofsky or Lansky performance status of
equal to or greater than 50 percent

- Disease status: Failure to respond to standard therapy (usually combination
chemotherapy with or without radiation and surgery) or development of progressive
disease at any time. Disease evaluable by MIBG scan must be present within 8 weeks of
study entry and subsequent to any intervening therapy. The principal or
co-investigator can waive the requirement for intervening therapy if in their judgment
this would pose undue risk and would not affect ability to judge treatment
effectiveness.

- Stem cells: Patients must have a hematopoietic stem cell product available for
re-infusion after MIBG treatment at doses of at least 12 mCi/kg. The recommended
minimum quantity for peripheral blood stem cells is 1.0 x 10^6 CD34+ cells/kg. The
minimum dose for bone marrow is 1.0 x 10^8 mononuclear cells/kg. If no stem cells are
available, the dose of 131 I-MIBG should be 12mCi/kg or less.

- Prior Therapy: Patients may enter this study with or without re-induction therapy for
recurrent tumor. Patients must have fully recovered from the toxic effects of any
prior therapy. Subjects cannot be receiving chemotherapy, cytokine therapy or other
investigational agents, and must have fully recovered from the toxic effects of any
prior therapy.

- Liver function: Bilirubin ≤2x upper limit of normal; AST/ALT ≤10x upper limit of
normal

- Kidney function: Creatinine ≤3x upper limit of normal

- Signed informed consent: The patient and/or the patient's legally authorized guardian
must provide written informed consent to participate in this expanded access protocol.

Exclusion criteria

- Patients with disease of any major organ system that would compromise their ability to
withstand therapy, as deemed by the principal investigator or treating
sub-investigator.

- Because of the teratogenic potential of the study medications, no patients who are
pregnant or lactating will be allowed. Patients of childbearing potential must
practice an effective method of birth control while participating on this study, to
avoid possible damage to the fetus.

- Patients who are on hemodialysis

- Patients with uncontrolled infections

- Exceptions to the above eligibility criteria may be allowed if approved by the
principal investigator as long as exception does not compromise the safety of the
subject and the exception is clearly documented. Each protocol exception must be
reviewed by the Institutional Review Board before therapy is initiated.