"NANT 2017-01: A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB FOR RELAPSED/REFRACTORY NEUROBLASTOMA"

131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most effective therapies utilized
for neuroblastoma patients with refractory or relapsed disease. In this pediatric phase 1
trial, 131I-MIBG will be given in combination with dinutuximab, a chimeric 14.18
monoclonal antibody. This study will utilize a traditional Phase I rolling 6 dose
escalation design to determine a recommended phase 2 pediatric dose. An expansion cohort
of an additional 6 patients will then be enrolled. If tolerable, vorinostat will then be
added to the third dose level. A 6 patient expansion cohort may then be enrolled.

Inclusion Criteria:

1. Patients must have evidence of MIBG uptake into tumor at ≥ 1 site (bone or soft
tissue) within 28 days prior to study entry and subsequent to any intervening
therapy.

2. Patients must have a diagnosis of neuroblastoma either by histologic verification of
neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
urinary catecholamines.

3. Patients must have a history of high-risk neuroblastoma according to COG risk
classification at the time of study registration. Patients who were initially
considered low or intermediate-risk, but then reclassified as high-risk are also
eligible.

4. All patients must have at least one of the following

1. Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma
at any time prior to enrollment regardless of response to frontline therapy

2. No prior history of recurrent/progressive disease since the diagnosis of high
risk neuroblastoma b1) Refractory disease- a best overall response of no
response/stable disease since diagnosis of high risk neuroblastoma and at least
4 cycles of induction therapy. No prior history of recurrent/progressive
disease since the diagnosis of high risk neuroblastoma.

b2) Persistent disease- a best overall response of no partial response since
diagnosis of high risk neuroblastoma and at least 4 cycles of induction
therapy. No prior history of recurrent/progressive disease since the diagnosis
of high risk neuroblastoma.

5. Patients must have at least ONE of the following (lesions may have received prior
radiation therapy as long as they meet the other criteria listed below):

a) For recurrent/progressive or refractory disease, at least one MIBG avid bone
site.

b) For persistent disease, if a patient has 3 or more MIBG avid lesions, then no
biopsy is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then
biopsy confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG
avid site present at the time of enrollment is required to be obtained at any time
point prior to enrollment.

c) For MIBG non-avid tumors, patients must have at least one FDG avid site and a
biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior
to enrollment from at least one FDG-avid site.

6. Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study
enrollment based on routine morphology with or without immunocytochemistry in at
least one sample from bilateral aspirates and biopsies.

7. At least one soft tissue lesion that meets criteria for a TARGET lesion as defined
by:

a) SIZE: Lesion can be accurately measured in at least one dimension with a longest
diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis. Lesions meeting size
criteria will be considered measurable.

b) In addition to size, a lesion needs to meet one of the following criteria except
for patients with parenchymal CNS lesions which only need to meet size criteria: b1)
MIBG avid. For patients with recurrent/progressive or refractory disease, no biopsy
is required. For patients with persistent disease only: If a patient has only 1 or 2
MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or
ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is
required to be obtained. If a patient has 3 or more MIBG avid lesions, then no
biopsy is required.

b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy
confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET
avid site present at the time of enrollment.

8. At least one non-target soft tissue lesion that is not measurable, but had a biopsy
positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid at any time
prior to enrollment.

9. Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years)
or Karnofsky (>16 years) score of at least 50.

10. Prior Therapy 1. Patients must have fully recovered from the acute toxic effects of
all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration.

2. Patients must not have received the therapies indicated below after disease
evaluation or within the specified time period prior to registration on this study
as follows:

1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior to
registration.

2. Biologic anti-neoplastics- agents not known to be associated with reduced platelet
or ANC counts (including retinoids): must not have received within 7 days prior to
registration.

3. Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives
whichever is longer, but no longer than 30 days (with recovery of any associated
toxicities), prior to protocol therapy.

4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.): must not
have received within 3 weeks and resolution of all toxicities.

5. Radiation: must not have received small port radiation within 7 days prior to
registration.

6. Hematopoietic Stem Cell Transplant: 7. IVIG 8. Therapeutic MIBG 9. Investigational
medicines covered under another IND 10. Medications interfering with MIBG uptake 11.
Medications that prolong QTc (Part B only) 12. Valproic acid (Part B only) 11) All
patients must have adequate organ function defined as:

- Hematological Function:

1. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL

2. Absolute Neutrophil count: ≥750/µL

3. Absolute Lymphocyte count ≥ 500/µL

4. Platelet count: ≥ 50,000/µL, transfusion independent (no platelet transfusions
within 1 week)

5. Hemoglobin ≥ 10 g/dL (may transfuse)

6. Patients with known bone marrow metastatic disease will be eligible for study as
long as they meet hematologic function criteria above.

- Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender
OR creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2

- Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and
SGOT (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS)
if present, must be stable or improving clinically

- Cardiac Function: Normal ejection fraction documented by either echocardiogram
or radionuclide MUGA evaluation OR Normal fractional shortening documented by
echocardiogram

- Pulmonary Function: No dyspnea at rest, no oxygen requirement.

12) Reproductive Status: All post-menarchal females must have a negative
beta-HCG. Males and females of reproductive age and childbearing potential
must use effective contraception for the duration of their participation.

13) Patients with other ongoing serious medical issues must be approved by the
study chair prior to registration.

14) Autologous peripheral blood stem cells (PBSC)•The minimum dose for
peripheral blood stem cells is 2.0 x 106viable CD34+ cells/kg. Patients
who do not meet this minimum requirement for available PBSCs are not
eligible. •Only un-purged stem cells are allowed unless a center has
separate FDA approval for infusion of purged stem cells. •For patients
whose body weight exceeds ideal body weight (IBW) by more than 20%,
adjusted body weight may be used for the calculation of PBSC dose 15)
Physician deems that there is reasonable ability to obtain vorinostat via
commercial supply (Part B Only)

Exclusion Criteria:

- Pregnancy, breast feeding, or unwillingness to use effective contraception during
the study.

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.

- Patients with disease of any major organ system that would compromise their ability
to withstand therapy.

- Patients who have received prior allogeneic stem cell transplant

- Patients who have received prior solid organ transplantation

- Patients must not have received prior total body irradiation

- Prior HDAC inhibitor given in combination with therapeutic 131I-MIBG(Part B only)

- The maximum total allowable dose of 131I-MIBG that can be given per institutional
guidelines must be at least 90% of the calculated 131I-MIBG dose or the patient is
not eligible.

- Patients who are on hemodialysis.

- Patients with an active or uncontrolled infection.

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C.

- Patient declines participation in NANT 2004-05, the NANT Biology Study

- Patients and/or families who are physically and psychologically unable to cooperate
with the radiation safety isolation.

- Patients with a history of having to discontinue anti-GD2 antibody therapy due to
toxicity are not eligible.

- Prior anti-GD2 therapy is not otherwise an exclusionary criteria unless it was given
in combination with therapeutic 131I-MIBG.