Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded
natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the
feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells
with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

Ch14.18 is a chimeric antibody against GD2, which is expressed on a majority of neuroblastoma
cells. It has been shown to increase EFS and OS in patients with high-risk neuroblastoma when
given after autologous stem cell transplant in combination with subcutaneous GM-CSF and
intravenous IL-2, followed by isotretinoin. Lenalidomide has been studied in children with
solid tumors and can safely be given to patients based on 2 prior trials in children. It was
also shown to have immunomodulatory effects and is synergistic with ch14.18. Lenalidomide is
also an oral agent that can be given in the outpatient setting. Natural killer cells are
lymphocytes of the innate immune system that have the ability to recognize and kill malignant
cells, including neuroblastoma. Ch14.18 and lenalidomide both exert part of their anti-cancer
effect through the activation of natural killer cells. Patients are being given in
combination in NANT 2011-04 where the safety and immunomodulatory effect has been established
in that study at the dose level proposed in this study. Natural killer cells are
dysfunctional and low in number in many cancer patients, and number and function are further
suppressed by chemotherapy and radiation. Investigators hypothesize that autologous NK cells
can be expanded and activated ex vivo and readministered to restore number and function, and
in combination with lenalidomide and ch14.18 will provide an anti-tumor effect in patients
with relapsed or refractory neuroblastoma.

Investigators will determine the feasibility of centralized expansion, cryopreservation, and
distribution of autologous NK cells. Investigators will then determine the maximum tolerated
dose by assessing the toxicities of autologous expanded NK cells given with ch14.18; by
assessing the toxicities, cytokinetics and immunomodulatory effects, Investigators will
select the recommended Phase II dose of the two-agent combination after dose escalation of
the NK cells and then adding lenalidomide to the combination to establish the three-agent
combination.

Cytokinetics (persistence of infused NK cells) and immune function studies will be required
for all patients entered on this study. In addition to routine assessment of response,
quantification of rare tumor cell detection in blood and bone marrow using TLDA will also
provide another measure of possible anti-tumor efficacy to support the rationale for the
final schedule chosen.

Inclusion Criteria:

- 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.

- 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.

- Patients must have at least ONE of the following:

1. Recurrent/progressive disease at any time prior to study enrollment

2. Refractory disease

3. Persistent disease

- 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):

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

2. For persistent disease, If a patient has only 1 or 2 MIBG avid lesions AND a
Curie Score of 1-2, then biopsy confirmation of neuroblastoma and/or
ganglioneuroblastoma in at least one site present at the time of enrollment (bone
marrow, bone, or soft tissue) is required to be obtained at any time point prior
to enrollment.

3. FDG-PET avid tumors: A biopsy confirmation of neuroblastoma and/or
ganglioneuroblastoma is required at any time prior to enrollment OR anatomical
imaging is required at the time of enrollment consistent with a bone metastasis
for at least one FDG-avid bone site.

- 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.

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

1. 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.

2. In addition to measurable size, a lesion needs to meet the following criteria:

1. MIBG avid. For patients with persistent disease only: If a patient has only
1 or 2 MIBG avid lesions ANDa Curie Score of 1 - 2, then biopsy confirmation
of neuroblastoma and/or ganglioneuroblastoma in at least one site present at
time of enrollment is required to be obtained.

2. MIBG non avid tumors: These patients require a biopsy done at any time prior
to enrollment confirming neuroblastoma and/or ganglioneuroblastoma in at
least one soft tissue site (even if FDG-PET avid) present at the time of
enrollment.

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

- 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.

- 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

- 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.

- 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.

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

- Patients may not receive any other anti-cancer agents or radiotherapy while on
protocol therapy.

- Ability to Swallow Pills

Exclusion Criteria:

- Pregnancy: Quantitative Serum B-HCG must be negative in girls who are post-menarchal.

- Breast feeding women are not eligible.

- Active or uncontrolled infection

- CNS metastasis.

- Hypersensitivity to thalidomide, including history of erythema nodosum if
characterized by a desquamating rash while taking thalidomide or similar drugs (dose
level 4 only).

- Patient declines participation in NANT 2004-05; unless the institution has been
granted special exemption from mandatory registration on NANT 2004-05 by the NANT
Operations Center.