Naxitamab and Sargramostim in Treating Patients with Relapsed or Refractory High-Risk Neuroblastoma

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dosage of naxitamab (hu3F8) when combined with sargramostim (GM-CSF). (Phase I)

II. Assess the activity of hu3F8 plus (+) GM-CSF in patients who have primary refractory disease in bone marrow (BM) by measuring response and by calculating progression-free survival (PFS). (Group 1) (Phase II)

III. Assess the impact of hu3F8+GM-CSF on PFS in patients in >= second (2nd) complete remission (CR), but at high risk of another relapse. (Group 2) (Phase II)

IV. Assess the activity of hu3F8+GM-CSF in patients who have secondary refractory disease in bone marrow (BM) by measuring response and by calculating progression-free rate at 2 years. (Group 3) (Phase II)

V. To evaluate the efficacy of hu3F8+GM-CSF when given in cycles every 1-2 months for up to 24 months, in patients with primary or secondary refractory osteomedullary high-risk neuroblastoma (HR-NB) by evaluating response to treatment according to the International Neuroblastoma Response Criteria (INRC) modified with 123I-MIBG criteria and following the use of fludeoxyglucose F-18 (18F FDG)-positron emission tomography (PET) for iobenguane (MIBG) non-avid lesions. (Phase II)

SECONDARY OBJECTIVES:

I. To study the pharmacokinetics of hu3F8 when combined with GM-CSF. (Phase I)

II. To assess activity of hu3F8 plus GM-CSF against HR-NB. (Phase I)

III. To quantitate pain during hu3F8 and GM-CSF treatment. (Phase I)

IV. To study markers of granulocyte-mediated cytotoxicity and natural killer (NK)-mediated cytotoxicity, anti-hu3F8 immunity, and anti-tumor immunity before and after treatment with hu3F8/GM-CSF. (Phase I)

V. To quantitate the response of marrow NB by quantitative reverse transcription-polymerase chain reaction (PCR). (Phase I)

VI. To evaluate the duration of response (DoR) from the date of first response. (In patients with primary or secondary refractory osteomedullary HR-NB treated with cycles of hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

VII. To evaluate the PFS from the start of hu3F8+GM-CSF treatment. (In patients with primary or secondary refractory osteomedullary HR-NB treated with cycles of hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

VIII. To evaluate human anti-human antibody (HAHA). (In patients with primary or secondary refractory osteomedullary HR-NB treated with cycles of hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

IX. To evaluate PFS from the start of hu3F8+GM-CSF treatment. (In patients in > 2nd CR/VGPR but at high risk of another relapse from the start of hu3F8+GM-CSF treatment) (Phase II)

X. Evaluate event free survival (EFS) from the start of hu3F8+GM-CSF treatment. (In patients in > 2nd CR/VGPR but at high risk of another relapse from the start of hu3F8+GM-CSF treatment) (Phase II)

XI. To evaluate the safety of hu3F8+GM-CSF by the incidence of adverse events (AEs) and serious adverse events (SAEs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. (In all patients) (Phase II)

EXPLORATORY OBJECTIVES:

I. Assess overall survival in patients with primary or secondary refractory HR-NB. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

II. Assess overall survival in in patients with HR-NB in >= 2nd CR/VGPR, but at high risk of

another relapse. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

III. Assess concomitant opioid administration. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

IV. Assess hospitalization days. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

V. Apply real-time quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) to test the hypothesis that the minimal residual disease (MRD) findings in BM after the first 2 cycles of hu3F8+GM-CSF have significant prognostic impact on outcome. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

VI. Apply real-time quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) to test the hypothesis that the MRD findings in cell free RNA (cfRNA) after the first 2 cycles of hu3F8+GM-CSF have significant prognostic impact on outcome. (In patients treated with hu3F8+GM-CSF every 1-2 months for up to 24 months) (Phase II)

OUTLINE: This is a phase I, dose-escalation study of naxitamab followed by a phase II study.

Patients receive sargramostim subcutaneously (SC) on days -4 to 5 and naxitamab intravenously (IV) over approximately 30-90 minutes on days 1, 3, and 5. Treatment repeats every 2-4 weeks for up to 24 months, or until 5 cycles after a major response (complete response [CR] or partial response [PR]) in the absence of disease progression or unacceptable toxicity. Sargramostim may be stopped if patients have a history of an allergy to sargramostim or develop an allergic reaction to sargramostim after starting therapy.

After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.