Naxitamab Added to Induction for Newly Diagnosed High-Risk Neuroblastoma

Inclusion Criteria:

1. 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:

2. Subjects with newly diagnosed neuroblastoma with INRGSS Stage M disease with eitherof the following features:

3. MYCN amplification (> 4-fold increase in MYCN signals as compared to referencesignals), regardless of additional biologic features; OR

4. 365 days to ≥ 547 days of age without MYCN amplification, but unfavorablebiologic features such as unfavorable histology (INPC) or diploid tumor (DNAindex=1) or the presence of any segmental chromosome aberration (SCA) (somaticcopy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p,or 17q); OR

5. Age > 547 days of age regardless of biologic features Subjects with newly diagnosed neuroblastoma with INRGSS Stage MS disease with eitherof the following:

6. MYCN amplification (> 4-fold increase in MYCN signals as compared to referencesignals); OR

7. 365 days to ≥ 547 days (18 months) of age without MYCN amplification, butunfavorable biologic features such as unfavorable histology (INPC) or diploidtumor (DNA index=1) or SCA as above Subjects with newly diagnosed neuroblastoma INRGSS Stage L2 disease with either ofthe following:

8. MYCN amplification (> 4-fold increase in MYCN signals as compared to referencesignals); OR

9. 18 months to <5 years of age without MYCN amplification, but with unfavorablehistology (INPC); OR

10. ≥5 years of age without MYCN amplification, but with undifferentiated or poorlydifferentiated INPC Subjects with newly diagnosed neuroblastoma INRGSS Stage L1disease that is incompletely resected with MYCN amplification. Subjects > 547 days of age initially diagnosed with INRGSS Stage L1, L2 or MSdisease who progressed to Stage M without prior chemotherapy may enroll within 4weeks of progression to Stage M. Subjects ≥ 365 days of age initially diagnosed with MYCN amplified INRGSS Stage L1disease who progress to Stage M without systemic therapy may enroll within 4 weeksof progression to Stage M.

11. Subjects must be age ≤ 21 years at initial diagnosis.

12. Subjects must be >12 months of age at enrollment.

13. Adequate cardiac function defined as:

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

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

16. Adequate liver function must be demonstrated, defined as:

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

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

19. Subjects must have adequate renal function defined as an estimated GlomerularFiltration rate (eGFR) as calculated from the Bedside Schwartz equation (in units ofmL/min/1.73 m2) or via radioisotope GFR of ≥ 70. The Bedside Schwartz equation is: [(0.413) X (Height in cm)] / SCr

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

21. 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.

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

Exclusion Criteria:

1. Subjects who are less than 1 year of age

2. Subjects who are 12-18 months of age with INRGSS Stage M and all stage L2 subjectswith favorable biologic features (i.e., nonamplified MYCN, favorable pathology, andDNA index > 1) are not eligible.

3. 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.

4. Treatment with immunosuppressive treatment (topical, inhaled and short-termemergency steroids excluded) within 4 weeks prior to enrollment

5. 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.

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

7. Subjects receiving any investigational drug concurrently.

8. 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

9. 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.