A Study of Therapeutic Iobenguane (131-I) for Relapsed, High-Risk Neuroblastoma Subjects

OPTIMUM (MIBG 2014-01) is a Phase II, single-arm, non-randomized, open-label study of
therapeutic 131I-iobenguane (131I-MIBG) for the treatment of neuroblastoma. The study will be
conducted in male and female subjects, greater than 1 year of age, with iobenguane avid,
relapsed, high-risk neuroblastoma.

Subjects will receive 18 mCi/kg of 131I-MIBG intravenously, and if the subject qualifies, the
subject will receive the second 18 mCi/kg 131I-MIBG treatment (no sooner than 6 weeks
following the first therapeutic 131I-MIBG treatment). Subject must have an overall response
of stable disease or better, as assessed by the Investigator, and meet certain predefined
criteria to receive the second treatment.

Following a screening period of up to 4 weeks, the duration in the study treatment phase for
an individual subject, who receives two treatments, is up to 22 weeks. For an individual
subject, who receives one treatment only, the duration of the treatment phase is 16 weeks. In
addition, there is a 2-year follow-up after the treatment phase, during which assessments
will be performed to assess disease progression, as well as record adverse events.

Inclusion Criteria:

1. Subjects with a diagnosis of iobenguane avid, relapsed, high-risk neuroblastoma based
on revised INRC criteria who have completed at least one cycle of induction and
consolidation therapy with an INRC criterion of partial response or better, and then
showed new progressive disease (revised INRC criteria progressive disease) as
described in Park, et al. (2017).This may include one or more of the following drugs:
cyclophosphamide or ifosfamide, cisplatin or carboplatin, vincristine, doxorubicin
(adriamycin), etoposide, topotecan, and/or busulfan and melphalan (sometimes used
during stem cell transplant) and/or immunotherapy. (If a subject is symptomatic and
for logistical reasons cannot be treated immediately with 131I-MIBG, 1 to 2 cycles of
"bridging chemotherapy" or immunotherapy will be permitted. If "bridging chemotherapy"
or immunotherapy is applied, approximately 4 weeks will be required for reassessment
of the baseline including tumor assessment.

2. Must be therapeutic 131I-MIBG naive.

3. All soft tissue lesions identified on CT/MRI scans must be iobenguane-avid lesions on
an iobenguane (123I) scan or any non iobenguane avid lesions biopsy proven to be
non-tumor lesions.

4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least
2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).

5. If a man, must agree to use an adequate contraception method as deemed appropriate by
the Investigator (e.g., vasectomy, condoms) or partner using effective contraception
and to not donate sperm during the study and for 90 days after receiving the last dose
of study drug.

6. If a woman of childbearing potential, have a negative serum pregnancy test result
prior to each dosing and, if sexually active, be practicing an effective method of
birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a
cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner
sterilization throughout the study.

7. Age at study entry ≥1 year.

8. Previous platelet transfusions are permitted, as long as the subject has a platelet
count ≥50,000/μL without transfusion support for at least 1 week.

9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.

10. An absolute neutrophil count ≥750/μL without growth factor for 5 days.

11. Liver function parameter results: total bilirubin ≤1.5 × upper limit of normal for
age, and serum glutamic-pyruvic transaminase (alanine aminotransferase) [SGPT (ALT)]
and serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) [SGOT (AST)]
<3 × upper limit of normal (note that for ALT, the upper limit of normal for all sites
is defined as 45 U/L).

12. Normal thyroid function as measured by T4 and TSH or have abnormal results that are
not considered clinically important by the Investigator or may be receiving
levothyroxine.

13. Cardiac Function: Ejection fraction (≥55%) documented by echocardiogram within 1 month
prior to Visit 1 (baseline).

14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance
Status Performance Status (for subjects 1 to 16 years of age) ≥50%.

15. Full recovery from the toxic effects of any prior therapy.

Exclusion Criteria:

1. Evidence of non-avid iobenguane lesions on iobenguane (123I) scan including soft
tissue disease on CT/MRI that is not iobenguane-avid.

2. Subjects with primary refractory disease.

3. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not
recovered from effects of any biologic therapy.

4. Subjects that are refractory to the prior treatment regimen.

5. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.

6. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit
1 are excluded. Those who have received allogeneic stem cell treatment more than 4
months from Visit 1 must have recovered and have no active graft versus host disease
(GVHD) to be eligible.

7. History of local radiation therapy within the last 3 months.

8. History of total body irradiation.

9. Subjects do not have adequate renal function defined as adjusted serum creatinine ≥1.5
× upper limit of normal for sex and age.

10. Subjects who are on hemodialysis.

11. Pregnancy or breastfeeding.

12. Significant active infections including active hepatitis B, or hepatitis C infection,
or known infection with human immunodeficiency virus (HIV) (testing for HIV is not
required prior to study entry).

13. Clinically important cardiac, pulmonary, and hepatic impairment.