131-I-MIBG Therapy for Refractory Neuroblastoma and Metastatic Pheochromocytoma (CHP-830)

Metaiodobenzylguanidine (MIBG) is a substance that is taken up by neuroblastoma or pheochromocytoma tumor cells. MIBG is combined with radioactive iodine (131 I)in the laboratory to form a radioactive compound 131 I-MIBG. This radioactive compound delivers radiation specifically to the cancer cells and causes them to die.

The purpose of this research is to gain further evidence of the effectiveness of this treatment and to further assess the side effects of 131 I- MIBG therapy.

General Description of the Medication Being Used on the Study:

Metaiodobenzylguanidine (MIBG) is a substance that is taken up by neuroblastoma or pheochromocytoma tumor cells. MIBG is combined with radioactive iodine (131I) in the laboratory to form the radioactive compound 131I-MIBG. The 131I-MIBG compound delivers radiation specifically to the neuroblastoma cancer cells and causes them to die. 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. A recent study using increasing doses of 131I-MIBG in both children and adults with relapsed neuroblastoma or metastatic pheochromocytoma 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, MIBG and or CT scan, an MRI, a bone scan, Bone marrow aspirate and biopsy, urine tests. Your doctor will determine which tests are required.

Before your child can begin treatment on this study, s/he will need to have an intravenous catheter (tube) placed in a vein. We can use an existing central venous catheter to administer the medicine.

Because your child's urine will be radioactive, a urinary catheter may be inserted through your child's urethra into the bladder 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.

1. Your child will be treated in a specially prepared room in the CHOP Pediatric Oncology Unit. Upon admission, the nursing staff will instruct you on the care you will give your child following the MIBG infusion. Because of the frequent exposure of the nursing staff to radiation and the high level of radiation surrounding your child during therapy, the nurses' contact will be limited to complex medical care, so that they are available for your child 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.
2. Isolation: For 2-5 days your child 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.
3. Your child 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.
4. Your child 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.
5. The 131I-MIBG will be given through an intravenous catheter over 1.0 - 2-hours.
6. During the administration of the drug, your child's blood pressure and heart rate will be checked frequently.
7. Before and at regular intervals after treatment, your child will have routine blood tests to check his/her blood counts, hormone, liver and kidney functions. Blood will be checked at least weekly or more (if indicated) for approximately 6 weeks after the treatment. Approximately 1 teaspoon of blood will be drawn weekly for 6 weeks to perform the tests listed above.
8. A 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).
9. Six to eight weeks after treatment, x-rays and other scans will be done to evaluate the response of the tumor to the treatment.
10. If your child's tumor is responding or stable 6-7 weeks after each treatment, s/he may be eligible for a second and third course of treatment, as long as his/her white blood counts have fully recovered from the treatment, without requiring the use of stem cells. 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.
11. If your child's blood counts decrease following the therapy, we will start Filgrastim (G-CSF). G-CSF is a medicine that helps increase the white blood cells. This is given by a subcutaneous (under the skin) injection (like an insulin shot) and needs to be taken daily. This medicine will start if the ANC (absolute neutrophil count, a measure of the infection fighting cells) goes below 750 and will continue until it rises above 5000. Your child may be given Neulasta 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. Neulasta will be given if your child's physician feels it is the right medicine for your child.

• Neuroblastoma (Relapsed or Refractory)
• Metastatic Pheochromocytoma

• Drug: 131 I-Metaiodobenzylguanidine (131 I-MIBG)
  131 I-MIBG 1-18mCi/kg given intravenously on day 1. Subjects may receive multiple courses every 4-8 weeks depending on the dose given.
  Other Names:

  • MIBG
  • 131 I-Metaiodobenzylguanidine
  • radioactive Iodine (131)
  • Metaiodobenzylguanidine
• Drug: 131 I-MIBG
  131-I-MIBG will be infused intravenously over 30-90 minutes once per course. The dose will be determined by the treating physician.
  Other Names:

  • 131 I- Metaidobenzylguanidine
  • MIBG
  • Radioactive iodine
  • Metaiodobenzylguanidine therapy

Inclusion Criteria:

• Refractory or relapsed neuroblastoma with original diagnosis based on tumor histopathology or elevated urine catecholamines with typical neuroblastoma cells in the bone marrow OR Metastatic 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
• Life expectancy: Patients must have a life expectancy of at least 8 weeks
• 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 (any new lesion or an increase in size of >25% of a pre-existing lesion). 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 12 mCi/kg. The minimum quantity for peripheral blood stem cells is 1.0 x 106 CD34+ cells/kg
• 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. At least 2 weeks should have elapsed since any chemotherapy causing myelosuppression and at least one week since any biologic agent or low-dose chemotherapy agent that does not cause myelosuppression. 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). Cytokine therapy (e.g. G-CSF, GM-CSF, IL-6, erythropoietin) must be discontinued a minimum or 24 hours prior to MIBG therapy.
• Liver function: Bilirubin ≤2x upper limit of normal; AST/ALT ≤10x upper limit of normal
• Kidney function: Creatinine ≤3x upper limit of normal
• Hematopoietic Criteria: ANC ≥750/L; Platelets ≥50,000/L without transfusion if stem cells are not available (any ANC or platelet allowed if stem cells available).
• Normal lung function as manifested by no dyspnea and/or no hypoxia greater than grade 3
• No clinically significant cardiac dysfunction
• Signed informed consent: The patient and/or the patient's legally authorized guardian must acknowledge in writing that consent 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. Any significant organ impairment should be discussed with the Study Chair or Vice Chair prior to patient entry.
• 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 that meet grade 3-4 toxicity criteria.