Anti-GD2 Monoclonal Antibody Hu14.18K322A and Combination Chemotherapy before Autologous Stem Cell Transplant and Radiation Therapy in Treating Younger Patients with Previously Untreated High-Risk Neuroblastoma

PRIMARY OBJECTIVES:

I. To study the efficacy (response: complete response [CR] + partial response [PR]) to two initial courses of cyclophosphamide and topotecan hydrochloride (topotecan) combined with anti-GD2 monoclonal antibody hu14.18K322A (hu14.18K322A) (4 doses/course followed by sargramostim [GMCSF]) in previously untreated children with high-risk neuroblastoma.

II. To estimate the event-free survival of patients with newly diagnosed high-risk neuroblastoma treated with the addition of hu14.18K322A to each phase of treatment (Induction, Consolidation, Experimental Minimal Residual Disease [MRD]* and MRD Treatment).

*Note: Experimental MRD phase deleted with Amendment 8.0

SECONDARY OBJECTIVES:

I. To study the feasibility of delivering hu14.18K322A to 6 cycles induction chemotherapy and describe the antitumor activity (CR + PR) of this 6 course induction therapy.

II. To estimate local control and pattern of failure associated with focal intensity modulated or proton beam radiation therapy dose delivery in high-risk abdominal neuroblastoma.

III. To describe the tolerability of four doses of hu14.18K322A with allogeneic natural killer (NK) cells from an acceptable parent, in the immediate post-transplant period (day +2 to +5 after peripheral blood stem cell [PBSC] infusion) in consenting participants.*

IV. To describe the tolerability of hu14.18K322A with aldesleukin (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as treatment for minimal residual disease (MRD).

*Note: Experimental MRD phase deleted with Amendment 8.0

EXPLORATORY OBJECTIVES:

I. To measure natural killer (NK) cell number and function during Induction, Intensification/Experimental MRD, and MRD/Maintenance.*

II. To measure T-lymphocyte subset number and function during Induction, Intensification/Experimental MRD, and MRD/Maintenance.*

III. To genotype natural killer (NK) cell receptors and measure their phenotype at diagnosis and after the initial six weeks of therapy, and to associate these features with treatment outcome.

IV. To describe the relative frequency of positive bone marrow and peripheral blood by sensitive minimal residual disease (MRD) methods at diagnosis, after the initial six weeks of therapy, at the time of stem cell harvest, and at several time points following the completion of intensification

V. To describe whether or not human anti-human antibodies (HAHA) develop in participants receiving hu14.18K322A.

VI. To procure tumor samples for construction of tissue microarray blocks that will be utilized in further biologic characterization of these tumors.

VII. To assess the feasibility of measuring plasma catecholamine metabolites in patients with known neuroblastoma and to obtain preliminary data on the possible utility of plasma catecholamine metabolite analyses in patients with neuroblastoma.

VIII. To determine the spectrum of host immune response against tumor by measuring the amount of CD8+ cytotoxic T-cells relative to Foxp3+ regulatory T-cells in tumor specimens.

IX. To assess the expression of PD-L1 by neuroblastoma tumor cells by applying antibodies directed against PD-L1 using fully automated immunohistochemical techniques.

X. To determine if there is a correlation between the number of Image Defined Risk Factors (as defined in the International Neuroblastoma Risk Group Staging System) and outcome of patients with high risk neuroblastoma.

XI. To perform a simple descriptive comparison of renal radiation doses and other adjacent normal tissues between photon intensity modulated radiation therapy (IMRT) techniques and proton beam radiation technique.

XII. To assess the ability to achieve the target systemic exposure of intravenous busulfan in patients with neuroblastoma undergoing stem cell transplant, and to explore possible associations between busulfan pharmacokinetic parameters and patient’s outcome (e.g., response, event-free survival and overall survival) and specific covariates (e.g., age, sex, race, weight).

*Note: Experimental MRD phase deleted with Amendment 8.0

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 30 minutes on days 1-5, topotecan hydrochloride IV over 30 minutes on days 1-5, anti-GD2 monoclonal antibody hu14.18K322A IV over 4 hours on days 2-5, and aldesleukin subcutaneously (SC) once daily (QD) on days 6, 8, 10, 12, 14, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo peripheral blood stem cell harvest (PBSCH) per standard operating procedure and undergo surgical resection.

INDUCTION THERAPY: Beginning weeks 6 and 12, patients receive cisplatin IV over 1 hour on days 1-4, etoposide IV over 1 hour on days 1-3, anti-GD2 monoclonal antibody hu14.18K322A IV over 4 hours on days 2-5, sargramostim SC beginning on day 7 and continuing until blood counts recover, and aldesleukin SC QD on days 6, 8, 10, 12, 14, and 16. Beginning weeks 9 and 15, patients receive cyclophosphamide IV over 6 hours on days 1-2, doxorubicin hydrochloride IV continuously on days 1-3, vincristine sulfate IV daily on days 1-3, anti-GD2 monoclonal antibody hu14.18K322A IV over 4 hours on days 2-5, sargramostim SC beginning on day 7 and continuing until blood counts recover, and aldesleukin SC QD on days 6, 8, 10, 12, 14, and 16. Patients unable to have their primary tumor resected after 2 courses undergo surgical removal.

INTENSIFICATION PHASE: Patients receive busulfan IV every 6 hours on days -6 to -3 and melphalan IV QD on days -2 to -1. Patients undergo autologous stem cell transplant on day 0.

MRD TREATMENT/MAINTENANCE: Patients receive anti-GD2 monoclonal antibody hu14.18K322A IV over 4 hours on days 3-6 (courses 1, 3, and 5), on days 7-10 (courses 2 and 4), sargramostim SC or IV QD on days 0-13, isotretinoin PO on days 11 to 24 (course 1), on days 10-23 (course 3 and 5) and twice daily (BID) on days 14-27 (courses 2-6 and 4), and aldesleukin IV continuously on days 10-4 3 and 7-10 (courses 2 and 4). Within 42 days of stem cell transplant, patients undergo intensity modulated radiation IMRT or proton beam therapy (IMRT) over 17-23 days.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then annually for 3 years.