The study participant is being asked to take part in this research study because the participant has been diagnosed with neuroblastoma that did not fully respond to previous treatment (refractory), or it has returned after treatment (relapsed).
Primary Aims
* To evaluate if the administration of N-803 in combination with irinotecan, temozolomide, hu14-18K322A, and GM-CSF in patients with relapsed/refractory neuroblastoma is feasible and tolerable * To determine if the response rate of N-803 with irinotecan, temozolomide, hu14.18K322A and GM-CSF in patients with relapsed/refractory neuroblastoma is superior to the combination of irinotecan, temozolomide, hu14.18K322A, and GM-CSF
Secondary Aims
* To describe the toxicity profile of N-803 administered with irinotecan, temozolomide, hu14.18K322A and GM-CSF * To evaluate and compare the progression free survival (PFS) and overall survival (OS) of and between patients receiving irinotecan, temozolomide, hu14.18K322A and GM-CSF with and without N-803
Patients must have high-risk neuroblastoma according to COG risk classification at the time of study registration. Patients whose disease was initially considered low or intermediate risk but were then reclassified as high-risk neuroblastoma prior to enrollment are also eligible.
Recurrent/progressive disease after the diagnosis of high-risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy. (Note that this excludes patients initially considered low or intermediate risk that progressed to high-risk disease but have not progressed after the diagnosis of high-risk neuroblastoma).
Refractory disease: A best overall response of no response/stable disease since diagnosis of high-risk neuroblastoma AND after at least 4 cycles of induction therapy.
Persistent disease: A best overall response of partial response since diagnosis of high-risk neuroblastoma AND after at least 4 cycles of induction therapy
None
Parallel
Temozolomide
DrugIV, Days 1-5
Irinotecan
DrugIV, Days 1-5
hu14.18K322A
DrugIV over 4 hours daily times 4 doses, Days 2-5.
N803
DrugSubcutaneous (SC), Day 6.
Sargramostim
DrugSubcutaneous injection (preferred) or IV, Days 7-13.
To evaluate if the administration of N-803 in combination with irinotecan, temozolomide, hu14-18K322A, and GM-CSF in patients with relapsed/refractory neuroblastoma is feasible
Feasibility Measures: Patients evaluable for toxicity in the safety run-in must receive one dose of N-803. The proportion of evaluable patients who successfully complete the protocol-defined treatment regimen in the Safety Run-in phase will be calculated. The reasons for treatment discontinuation or deviations from the protocol will be summarized.
To determine if the response rate of N-803 with irinotecan, temozolomide, hu14.18K322A and GM-CSF in patients with relapsed/refractory neuroblastoma is superior to the combination of irinotecan, temozolomide, hu14.18K322A, and GM-CSF
Tolerability Assessments: Tolerability of the protocol-defined treatment in the Safety Run-in phase will be determined by assessing adverse events and their severity. Adverse events will be categorized based on standard CTCAE v5.0 criteria. Dose modifications or interruptions resulting from treatment-related adverse events will be analyzed.
To determine if the response rate of N-803 with irinotecan, temozolomide, hu14.18K322A and GM-CSF in patients with relapsed/refractory neuroblastoma is superior to the combination of irinotecan, temozolomide, hu14.18K322A, and GM-CSF
Tumor response will be assessed using standard NANT criteria. The primary endpoint for response analysis will be Best Overall Response (BOR), defined as the best response observed prior to progression, cross over or start of another therapy. Point estimates for the response rate (proportion of patients who have BOR of PR or better) will be calculated, together with exact 95% confidence intervals.
To describe the toxicity profile of N-803 administered with irinotecan, temozolomide, hu14.18K322A and GM-CSF
Toxicities will be graded using CTCAE v5.0. The toxicity profile will be defined as a comprehensive assessment of adverse events, categorized by standard toxicity criteria. The frequency, type, and severity and attribution of adverse events will be calculated and summary statistics for the toxicity profile will be provided.
To evaluate and compare the progression free survival (PFS) of and between patients receiving irinotecan, temozolomide, hu14.18K322A and GM-CSF with and without N-803
Progression-Free Survival (PFS) is defined as the time from the start of treatment to disease progression or death from any cause. Time from the day of receiving irinotecan, temozolomide, hu14.18K322A and GM-CSF with and without N-803 to the day of development of any progression or death will be assessed by the Kaplan-Meier method separately. The PFS rate will be estimated along with the corresponding 95% CI. A log-rank test will be used to compare between the two groups with and without N-803.
To evaluate and compare overall survival (OS) of and between patients receiving irinotecan, temozolomide, hu14.18K322A and GM-CSF with and without N-803
Overall Survival (OS) is defined as the time from the start of treatment to death from any cause. Time from the day of receiving irinotecan, temozolomide, hu14.18K322A and GM-CSF with and without N-803 to the day of development of any progression or death will be assessed by the Kaplan-Meier method separately. The OS rate will be estimated along with the corresponding 95% CI. A log-rank test will be used to compare between the two groups with and without N-803.
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