Expanded Access Protocol Using 131I-MIBG Therapy for Refractory Neuroblastoma, Pheochromocytoma, or Paraganglioma

Neuroblastoma, pheochromocytoma, and paraganglioma remain fatal diseases for a large
percentage of patients, especially those with high-risk disease features who become resistant
to conventional therapy. 131I-metaiodobenzylguanidine (131I-MIBG) is a norepinephrine analog
that concentrates in adrenergic tissue and has been shown to be sensitive and specific for
detecting localized and metastatic neuroblastoma, pheochromocytoma, and paraganglioma. More
importantly, experience of many institutions has proven that this agent used as a targeted
radiotherapeutic has significant anti-tumor activity against refractory neuroblastoma 1-7 as
well as pheochromocytoma and paraganglioma. Children's Hospital of Philadelphia, UCSF, and
the University of Michigan have just completed a large Phase 2 study of 131I-MIBG given in
doses of 10-18 mCi/kg with stem cell rescue, if necessary, and have shown that this agent is
safe and effective palliative therapy for refractory or relapsed neuroblastoma patients. In
addition, there is growing evidence that low-dose (5-10 mCi/kg) submyeloablative MIBG therapy
is both safe and effective for disease palliation. This protocol therefore provides a
mechanism to deliver this therapy when clinically indicated.

Primary Objectives:

- Provide palliative therapy with 131I-MIBG for patients with advanced neuroblastoma,
pheochromocytoma, or paraganglioma.

- Gain more information about acute and late toxicity of 131I-MIBG therapy for patients
with refractory neuroblastoma, pheochromocytoma, or paraganglioma.

Inclusion Criteria:

- Diagnosis: Refractory/Relapsed neuroblastoma with original diagnosis based on tumor
histopathology or elevated urine catecholamines with typical tumor cells in the bone
marrow, OR pheochromocytoma or paraganglioma not amenable to curative surgery

- Age ≥ 12 months and able to cooperate with radiation safety restrictions during
therapy period with/without pharmacologic anxiolysis.

- Disease status: Failure to respond to standard therapy (usually combination
chemotherapy with/without radiation and surgery) or development of progressive disease
at any time (any new lesion or an increase in size of > 25% of a pre-existing lesion).
Disease evaluation must be completed within 8 weeks of study entry. If possible, the
disease evaluation should take place subsequent to intervening therapy; if intervening
therapy does occur, evaluations should be done as clinically indicated. If patient has
received prior treatment with MIBG, they must have a response or stable disease after
the most recent MIBG infusion. Patient may have PD after showing initial response to
MIBG therapy (at [or around] the day 35-63 post-MIBG therapy evaluation).

- Patients must have a hematopoietic stem cell product available for re-infusion after
131I-MIBG treatment at doses of ≥ 12 mCi/kg. If no stem cells are available, then the
dose of 131I-MIBG should be < 12 mCi/kg.

- The minimum quantity for purged or unpurged peripheral blood stem cells (PBSC) is
1.5 x 10e6 viable CD34+ cells/kg (recommended 2 x 10e6 viable CD34+ cells/kg).

- The minimum dose for bone marrow is 1.0 x 10e8 mononuclear cells/kg (optimum >
2.0 x 10e8 mononuclear cells/kg).

- Prior Therapy: Patients may enter this study with/without re-induction therapy for
recurrent tumor. Patients must have fully recovered from the toxic effects of any
prior therapy, meeting the following criteria: At least 2 weeks should have elapsed
since any anti-tumor therapy and the patient must meet hematologic criteria below.
Three-months should have elapsed in the case of completing radiation to any of the
following fields: craniospinal, total abdominal, whole lung, total body irradiation
(spot irradiation to skull-based metastases is NOT considered craniospinal radiation
for the purposes of this study. Cytokine therapy must be discontinued a minimum of 24
hours prior to 131I-MIBG therapy.

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

- Serum Creatinine ≤ 2x upper limit of normal OR 24-hr creatinine clearance OR GFR ≥ 60
ml/min/1.73m2(For example, a patient would meet this criteria if GFR < 60
ml/min/1.73m2 but serum creatinine ≤ 2x upper limit of normal.)

- ANC ≥ 750/µL; Platelets ≥ 50,000/µL without transfusion if stem cells are not
available (ANC ≥ 500 and any platelet count allowed if stem cells available). Patient
must be off myeloid growth factors for at least 24 hours. If the patient has received
prior treatment with MIBG, they may be thrombocytopenic, but requiring no more than 2
platelet transfusions per week to maintain counts above 20,000. Hemoglobin must be ≥
10 gm/dL (transfusion allowed) regardless of stored stem cell availability.

- Normal lung function as manifested by no dyspnea at rest or exercise intolerance, no
oxygen requirement

- No clinically significant cardiac dysfunction

- Signed informed consent/assent: The patient and/or the patient's legally authorized
guardian must acknowledge in writing that consent/assent to become a study subject has
been obtained, in accordance with institutional policies approved by the U.S.
Department of Health and Human Services.

Exclusion Criteria:

- Patients with disease of any major organ system that would compromise their ability to
withstand therapy. Significant organ impairment should be discussed with the Principal
Investigator prior to patient entry.

- 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. Abstinence is an effective method
of birth control.

- Patients who are on hemodialysis

- Proteinuria, in the absence of urinary infection, within 4 weeks prior to the planned
treatment date is a relative contraindication to receiving therapy for patients with
pheochromocytoma/paraganglioma. Patients with pheochromocytoma/paraganglioma with any
proteinuria must have a 24-hr urine protein determination. If proteinuria is confirmed
as being above the institutional upper limit of normal, the patient is ineligible for
MIBG therapy.

- Patients with active infections that meet grade 3-4 according to the NCI CTCAE v4.0.

- Patients with known MIBG-avid parenchymal brain metastases are not eligible. (Patients
with leptomeningeal or skull-based metastases are eligible.)