Activated T Cells Armed With GD2 Bispecific Antibody in Children and Young Adults With Neuroblastoma and Osteosarcoma

PRIMARY OBJECTIVES:

I. To perform a phase I dose-escalation study in patients with recurrent or refractory
neuroblastoma (NB) and other GD2-positive tumors to evaluate the safety and tolerability and
to determine the maximum tolerated dose (MTD) for anti-CD3 x hu3F8 bispecific antibody
(GD2Bi)-armed activated T cells (aATC) infused twice a week for a total of eight infusions in
combination with daily IL-2 (300,000 IU/m^2/day) and GM-CSF (250 ug/m^2 twice per week) in a
standard 3 + 3 dose escalation schema with 40, 80, and 160 x 10^6 cells/kg/infusion dose
levels.

II. To conduct a phase II clinical trial to explore efficacy and confirm the toxicity profile
of GD2Bi-aATC combined with IL-2 and GM-CSF in a phase II expansion cohort of 22 patients
with neuroblastoma (NB) using MTD determined in the phase I.

SECONDARY OBJECTIVES:

I. Evaluate immune responses in the phase I/II trial by sequential monitoring of anti-NB
cytotoxicity of peripheral blood lymphocytes and IFN-gamma EliSpots directed at NB lines.

II. To evaluate persistence of aATC in the blood and tumor biopsies by staining for murine
IgG2a to confirm trafficking of armed T cells to tumor.

III. To conduct exploratory study of (18F FDG) positron emission tomography (PET)/computed
tomography (CT) after armed ATC infusions in selected patients with PET/CT measurable soft
tissue and skeletal lesions.

OUTLINE: This is a phase I, dose-escalation study of OKT3/humanized 3F8 bispecific
antibody-aATC followed by a phase II study.

Patients receive IL-2 subcutaneously (SC) daily on days -2 to 35, sargramostim SC twice
weekly for 4 weeks, and OKT3/humanized 3F8 bispecific antibody-aATC intravenously (IV) over
30 minutes twice weekly for 4 weeks.

After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months.

The study is now in the phase II expansion phase.

Inclusion Criteria for phase II:

- The target tumor is limited to neuroblastoma and the diagnosis should be
histologically verified.

- Patients must have refractory or recurrent malignancy; patient's current disease state
must be one for which no known curative therapy is available;

- Patients should not receive any other experimental or phase 1 therapy within 3 weeks
prior to study enrollment and monoclonal antibody therapy within 6 weeks

- To be eligible for phase I study patients should have primary refractory or relapsed
disease as evidenced by:

- Local tumor recurrence measurable on CT or magnetic resonance imaging (MRI) scans
with or without metastatic lesions

- Refractory bone marrow involvement in patients with NB

- NB with MIBG-positive skeletal lesions

- The presence of radiographically measurable disease immediately prior to start of
Phase I immunotherapy is not an eligibility requirement in the following situations:

- In patients with NB who have documented bone marrow (BM) involvement;

- In patients with NB who have MIBG-positive bony lesion(s);

- An additional eligibility requirement for phase II study includes the presence of
radiographically measurable disease with the exception of MIBG-positive NB or NB with
bone marrow involvement:

- Patients must have a Lansky or Karnofsky performance status score of >= 70

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy

- Myelosuppressive chemotherapy: must not have received within 3 weeks of starting
immunotherapy (IT)

- Hematopoietic growth factors: at least 7 days since the last dose of growth
factor therapy

- Immunotherapy: at least 6 weeks must have elapsed since prior therapy that
includes a monoclonal antibody

- Normal organ function

- All patients or their parents or legal guardians must sign a written informed consent;
assent, when appropriate, will be obtained according to institutional guidelines

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

Exclusion Criteria:

- Patients who are pregnant or breast-feeding are not eligible for this study; negative
pregnancy tests must be obtained in girls who are postmenarchal; males or females of
reproductive potential may not participate unless they have agreed to use an effective
contraceptive method for the duration of study therapy and for 3 months after the last
dose of GD2Bi-aATC; breastfeeding women should be excluded

- Patients who have an uncontrolled infection are not eligible

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