Study of DFMO in Combination With Bortezomib for Relapsed or Refractory Neuroblastoma

Inclusion Criteria:

- Age: ≤ 21 years at the time of diagnosis.

- Diagnosis: Histologic verification at either the time of original diagnosis or relapse
of neuroblastoma.

- Disease Status: For the purposes of this study, aggressive multidrug chemotherapy is
defined as chemotherapy including 2 or more agents that must include an alkylating
agent and a platinum-containing compound. Patients must have ONE of the following:

- First episode of recurrent disease following completion of aggressive multi-drug
frontline therapy.

- First episode of progressive disease during aggressive multi-drug frontline therapy.

- Primary resistant/refractory disease detected at the conclusion of at least 4 cycles
of aggressive multidrug induction chemotherapy on or according to a high-risk
neuroblastoma protocol (examples include Children's Oncology Group trials: A3973,
ANBL0532, ANBL09P1, etc.).

- Measurable or evaluable disease, including at least one of the following: Measureable
tumor by CT or MRI; or A positive MIBG or PET scan; or Positive bone marrow
biopsy/aspirate.

- Current disease state must be one for which there is currently no known curative
therapy or no additional therapies proven to prolong survival with an acceptable
quality of life.

- A negative urine pregnancy test is required for female subjects of child bearing
potential (onset of menses or ≥13 years of age).

- Organ Function Requirements:

1. Subjects must have adequate liver function as defined by:

- AST and ALT <5x upper limit of normal

- Serum bilirubin must be ≤ 2.0 mg/dl

2. Subjects must have adequate Bone Marrow function defined as:

For patients without bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) ≤ 750/uL

- Platelet count 50,000/uL (transfusion independent, defined as not receiving platelet
transfusions within a 7 day period prior to enrollment. Exception: Patients that are
platelet dependent due to previous extensive treatment- e.g. - MIBG therapy).

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) Patients known to have bone
marrow involvement with neuroblastoma are eligible provided that minimum ANC and
platelet count criteria are met but are not evaluable for hematological toxicity.

- Subjects must have adequate renal function defined as: Serum creatinine based on
age/gender.

- Informed Consent: All subjects and/or legal guardians must sign informed written
consent. Assent, when appropriate, will be obtained according to institutional
guidelines.

Exclusion Criteria:

- Lansky score <50%

- BSA (m2) of <0.25

- Prior Therapy- Patients must have fully recovered from the acute toxic effects of all
prior anti- cancer chemotherapy and be within the following timelines:

1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of
enrollment onto this study (6 weeks if prior nitrosourea).

2. Hematopoietic growth factors: At least 5 days since the completion of therapy
with a growth factor.

3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent. For agents that have known adverse events occurring beyond
7 days after administration, this period must be extended beyond the time during
which adverse events are known to occur. The duration of this interval must be
discussed with the Study Chair.

4. Immunotherapy: At least 6 weeks since the completion of any type of
immunotherapy, e.g. tumor vaccines.

5. Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must
have elapsed since prior treatment with a monoclonal antibody.

6. XRT: At least 14 days since the last treatment except for radiation delivered
with palliative intent to a non-target site.

7. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and
≥ 2 months must have elapsed since transplant.

- Investigational Drugs: Subjects who have received another investigational drug within
the last 14 days are excluded from participation.

- Infection: Subjects who have an uncontrolled infection are not eligible until the
infection is judged to be well controlled in the opinion of the investigator.

- Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study, or in whom compliance is likely to be
suboptimal, should be excluded.