Naxitamab Added to Induction for Newly Diagnosed High-Risk Neuroblastoma

Inclusion Criteria:

• Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumorcells in bone marrow with elevated urinary catecholamine metabolites. Subjects withthe following disease stages at diagnosis are eligible, if they meet the otherspecified criteria: a) Subjects with newly diagnosed neuroblastoma with International NeuroblastomaStaging System (INSS) Stage 4 are eligible with the following: i. Age > 18 months (> 547 days) regardless of biologic features or ii. Age 12-18 months (365-547 days)with any of the following 3 unfavorable biologic features (MYCN amplification,unfavorable pathology and/or DNA index = 1) or iii. MYCN amplification (> 4-foldincrease in MYCN signals as compared to reference signals), regardless of age oradditional biologic features. b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible withthe following: i. MYCN amplification (> 4-fold increase in MYCN signals as comparedto reference signals), regardless of age or additional biologic features or ii. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status. c) Subjects with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCNamplification (> 4-fold increase in MYCN signals as compared to reference signals),regardless of age or additional biologic features.

• Subjects must be age ≤ 21 years at initial diagnosis

• Subjects must be >12 months of age at enrollment

• Ability to tolerate Peripheral blood stem cell (PBSC) collection: No knowncontraindication to PBSC collection. Examples of contraindications would include aweight or size less than that determined to be feasible at the collectinginstitution, or a physical condition that would limit the ability of the child toundergo apheresis catheter placement (if necessary) and/or the apheresis procedure.

• Adequate Cardiac Function Defined As:

1. Shortening fraction of ≥ 27% by echocardiogram, or

2. Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.

• Adequate liver function must be demonstrated, defined as:

1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND

2. ALT (SGPT) < 5 x upper limit of normal (ULN) for age

• Subjects must have adequate renal function defined as a serum creatinine based onage/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4

• A negative serum pregnancy test is required for female participants of childbearingpotential (≥13 years of age or after onset of menses)

• Both male and female post-pubertal study subjects must be willing to use a highlyeffective contraceptive method (i.e., achieves a failure rate of <1% per year whenused consistently and correctly) from the time of informed consent until 6 monthsafter study treatment discontinuation. Such methods include: combined (estrogen andprogestogen containing) hormonal contraception associated with inhibition ofovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraceptionassociated with inhibition of ovulation (oral, injectable, implantable),intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateraltubal occlusion, vasectomized partner, sexual abstinence.

• Informed Consent: All subjects and/or legal guardians must sign informed writtenconsent. Assent, when appropriate, will be obtained according to institutionalguidelines.

Exclusion Criteria:

• Subjects who are less than 1 year of age

• Subjects who are 12-18 months of age with INSS Stage 4 and all stage 3 subjects withfavorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNAindex > 1) are not eligible.

• Subjects who have had prior systemic therapy except for localized emergencyradiation to sites of life-threatening or function-threatening disease and/or nomore than 1 cycle of chemotherapy per a low or intermediate risk neuroblastomaregimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCNamplification status and histology.

• Treatment with immunosuppressive treatment (local steroids excluded) within 4 weeksprior to enrollment

• Inadequate pulmonary function defined as evidence of dyspnea at rest, exerciseintolerance, and/or chronic oxygen requirement. In addition, room air pulse oximetry < 94% and/or abnormal pulmonary function tests if these assessments are clinicallyindicated.

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study.)

• Subjects receiving any investigational drug concurrently.

• Subjects with any other medical condition, including but not limited tomalabsorption syndromes, mental illness or substance abuse, deemed by theInvestigator to be likely to interfere with the interpretation of the results orwhich would interfere with a subject's ability to sign or the legal guardian'sability to sign the informed consent, and subject's ability to cooperate andparticipate in the study.

• Subjects with a significant intercurrent illness (any ongoing serious medicalproblem unrelated to cancer or its treatment) that is not covered by the detailedexclusion criteria and that is expected to interfere with the action ofinvestigational medicinal products (IMPs) or to significantly increase the severityof the toxicities experienced from trial treatment.