Neuroblastoma Clinical Trials

• Patients must be ≥ 1 year of age and ≤ 30 years of age at the time of study enrollment

• Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e. \> 2 x upper limit of normal \[ULN\]), at the time of initial diagnosis

• Progressive/relapsed or refractory (defined as persistent disease with overall response no better than minor response \[MR\] to prior therapy per revised International Neuroblastoma Response Criteria \[INRC\]) neuroblastoma based on the revised INRC

• Patients must meet ONE of the following criteria:

‣ Primary refractory disease

• Primary refractory disease following chemoimmunotherapy as part of induction therapy (e.g., ANBL17P1, ANBL2131 Arm B). Patients with primary refractory disease must have received at least 4 cycles of frontline high-risk induction chemoimmunotherapy

∙ Primary refractory disease following aggressive multi-drug induction chemotherapy on or according to a high-risk NB protocol (e.g., A3973, ANBL0532, ANBL09P1, ANBL12P1, ANBL1531, or ANBL2131 Arm A) with persistent disease at the conclusion of at least 4 cycles of chemoimmunotherapy used as extended induction or pre-consolidation intensification of therapy for primary refractory disease (e.g., ANBL2131 Arm A with extended induction, ANBL1221, or ANBL1821)

⁃ NOTE: Patients who experienced disease progression either during or within 30 days of completion (last day of anti-GD2 antibody) of chemoimmunotherapy during induction or extended induction are not eligible for the study

⁃ Relapsed/progressive disease

• First episode of recurrence following chemoimmunotherapy as part of induction therapy (e.g., ANBL17P1, ANBL2131 Arm B) or extended induction (e.g., ANBL2131 Arm A)

⁃ NOTE: Patients who experienced disease progression either during or within 30 days of completion (last day of anti-GD2 antibody) of chemoimmunotherapy during induction or extended induction are not eligible for the study

∙ First episode of recurrent/progressive disease detected during or following chemoimmunotherapy used as part of post-consolidation therapy (e.g., ANBL19P1)

∙ Second episode of recurrent/progressive disease detected during or following chemoimmunotherapy used as first-line salvage therapy for recurrent or progressive disease (e.g., ANBL1221, ANBL1821). Patients with stable disease after receiving chemoimmunotherapy for first relapse are not eligible (must be primary refractory disease)

• Evaluable or measurable disease per the revised INRC

‣ Measurable soft tissue disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 that is metaiodobenzylguanidine (MIBG) avid or demonstrates increased FDG uptake on PET scan

⁃ Evaluable disease is defined as either:

• MIBG-avid lesions only (detected on MIBG scan with positive uptake at minimum of one site that do not meet criteria for measurable disease. This site(s) must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction). OR

∙ New bone site that is avid for FDG-PET (MIBG non-avid tumors) AND has CT/MRI findings consistent with tumor OR has been confirmed by biopsy

⁃ Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma to be considered a site of disease. Biopsy is not required for patients who have a new site of soft tissue disease or radiographic evidence of disease progression regardless of whether progression occurs while receiving therapy or after completion of therapy

• NOTE: Patients with bone marrow only disease are not eligible. Patients with only elevated catecholamines (i.e. \> 2 x ULN) are also not eligible for this study

• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age

• For the purposes of this study, chemoimmunotherapy is defined as a regimen utilizing any anti-GD2 antibody in combination with cytotoxic chemotherapy, with doses of chemotherapy similar to those used in ANBL1221, ANBL1821, ANBL17P1, ANBL2131, and ANBL19P1

• Patient must have received one and NO MORE THAN one prior chemoimmunotherapy-containing regimen

‣ NOTE: Patients who received ANBL2131 Arm B therapy or a similar regimen including anti-GD2 antibody in combination with chemotherapy and then received an extended induction with chemoimmunotherapy (regardless of whether the chemoimmunotherapy was administered for relapse, progression, or poor end of induction response) will be considered to have received two regimens of chemoimmunotherapy. Similarly, patients who receive chemoimmunotherapy during induction or extended induction and then receive chemoimmunotherapy in post-consolidation (e.g., per ANBL19P1) will be considered to have received two regimens of chemoimmunotherapy. These patients are not eligible for this trial

• Patient cannot have received more than two prior lines of therapy, including frontline therapy

‣ Standard high-risk induction with or without extended induction followed by consolidation and post-consolidation immunotherapy with or without eflornithine (DFMO) continuation therapy will be considered one line of therapy

⁃ ANBL2131 Arm B induction without extended induction followed by consolidation and post-consolidation immunotherapy with or without DFMO continuation therapy will be considered one line of therapy

• NOTE: Induction on ANBL2131 Arm B extended induction, and post-consolidation chemoimmunotherapy are each considered separate regimens for the purposes of counting the number of chemoimmunotherapy regimens. In addition, patients who received ANBL2131 Arm B therapy or a similar regimen including anti-GD2 antibody in combination with chemotherapy who received another line of relapse therapy following Arm B or similar treatment are also not eligible

⁃ In the relapse setting, one line of therapy will be considered at least one delivered cycle of chemoimmunotherapy (with no limit on the number of consecutive cycles of chemoimmunotherapy)

• NOTE: A change in the chemotherapy regimen or anti-GD2 antibody will be considered an additional line of chemoimmunotherapy and these patients will not be eligible for the trial

⁃ In the refractory setting where chemoimmunotherapy was used as extended induction or pre-consolidation intensification of therapy for primary refractory disease, one line of therapy will be considered at least 4 delivered cycles of chemoimmunotherapy (with no limit on the number of consecutive cycles of chemoimmunotherapy)

• NOTE: A change in the chemotherapy regimen or anti-GD2 antibody will be considered an additional line of chemoimmunotherapy and these patients will not be eligible for the trial

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Myelosuppressive chemotherapy: Must not have received within 14 days (2 weeks) of entry onto this study

• Biologic (anti-neoplastic agent): Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or ANC counts): ≥ 7 days after the last dose of agent. See Developmental Therapeutics Committee (DVL) homepage for commercial and Phase 1 investigational agent classifications

• Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade ≤ 1

• Radiation therapy (RT):

‣ ≥ 7 days must have elapsed from small port radiation; ≥ 12 weeks must have elapsed from large field radiation therapy (i.e., total body irradiation, craniospinal, whole abdominal, total lung, \> 50% marrow space); ≥ 6 weeks from other substantial bone marrow radiation

⁃ Lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma. Palliative radiation while on study is not permitted

• Stem cell transplant (SCT): Patients are eligible ≥ 6 weeks after autologous stem cell transplants or stem cell infusions (including stem cell infusions given as supportive care following iobenguane I-131 \[131I-MIBG\] therapy) as long as hematologic and other eligibility criteria have been met

• 131I-MIBG therapy: Patients who previously received 131I-MIBG therapy for relapsed/refractory disease or poor end of induction response are not eligible

‣ Prior receipt of 131I-MIBG therapy as part of planned frontline Induction therapy (e.g., ANBL09P1, ANBL1531) is allowed. Patients are eligible ≥ 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met

• Growth factor: Patients must not have received long-acting myeloid growth factors (e.g. pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor or platelet growth factor/stimulating agents (e.g., romiplostim, eltrombopag)

• Intravenous immunoglobulin (IVIG): Patients must not have received IVIG within 14 days of study entry

• Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (performed within 7 days prior to enrollment)

‣ Patients known to have bone marrow involvement with neuroblastoma are eligible provided that the minimum ANC and transfusion independent platelet count criteria are met

• Platelet count ≥ 100,000/uL (transfusion independent) (performed within 7 days prior to enrollment)

‣ Patients known to have bone marrow involvement with neuroblastoma are eligible provided that the minimum ANC and transfusion independent platelet count criteria are met

• A serum creatinine based on age/sex as follows: (performed within 7 days prior to enrollment)

‣ Age: 1 to \< 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) 0.6 (female)

⁃ Age: ≥ 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female) OR - a 24-hour urine creatinine clearance ≥ 60 mL/min/1.73 m\^2 OR - a glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2. If used for eligibility, GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)

⁃ Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age or ≤ 3.0 mg/dL for patients with documented Gilbert's syndrome (performed within 7 days prior to enrollment)

• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) ≤ 135 U/L (performed within 7 days prior to enrollment)

‣ Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• Shortening fraction of ≥ 27% by echocardiogram (ECHO), OR ejection fraction of ≥ 50% by ECHO or grated radionuclide study (obtained within 21 days prior to enrollment and start of protocol therapy)

• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry \> 94% if there is a clinical indication for pulse oximetry. Normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung for carbon monoxide \[DLCO\]) are required if there is a clinical indication for determination. For patients who do not have respiratory symptoms, full pulmonary function testing (PFTs) are NOT required (obtained within 21 days prior to enrollment and start of protocol therapy)

• Patients with a history of central nervous system (CNS) metastatic disease must have no clinical or radiological evidence of active CNS disease at the time of study enrollment. Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled

• CNS toxicity ≤ grade 2