Summary

This is a prospective, multicenter clinical trial in subjects with newly diagnosed
high-risk neuroblastoma to evaluate the efficacy and safety of administering naxitamab
with standard induction therapy. The initial chemotherapy will include 5 cycles of
multi-agent chemotherapy. Naxitamab will be added to all 5 Induction cycles. We
hypothesize that the addition of anti-GD2 therapy to induction chemotherapy will result
in improved end of induction responses and improved survival.

Objectives

This is a prospective, multicenter clinical trial in subjects with newly diagnosed
high-risk neuroblastoma to evaluate the efficacy and safety of administering naxitamab
with standard induction therapy.

All subjects will be followed for disease response, event free survival, overall survival
and toxicity. Extent of disease will be measured and assessed for changes throughout the
course of the study. All efficacy analyses will be performed on the evaluable population
which will consist of all enrolled subjects (subjects who initiate treatment with
naxitamab in combination with GM-CSF plus standard induction therapy) and who have
measurable disease at baseline.

The initial chemotherapy Induction regimen will utilize sequential administration of 5
cycles of multi-agent chemotherapy. Naxitamab will be added to all 5 Induction cycles.

Stem cell mobilization and collection will occur after the 2nd cycle of induction.

Surgical resection of the primary tumor will ideally occur after the 4th cycle of
Induction but may be delayed until after the 5th cycle of Induction if medically
necessary.

Disease status evaluations will occur at the following time points: (1) pre-treatment,
(2) post Cycle 2 Induction (3) Prior to surgical resection (if performed), (4) End of
Induction (which includes surgery and 5 cycles of chemotherapy), and (5) End of
Additional/Salvage Therapy as needed.

The current standard of care for high-risk neuroblastoma involves 5-7 cycles of induction
chemotherapy with surgical removal of the tumor after 4-5 cycles of chemotherapy,
followed by high-dose chemotherapy plus autologous stem cell transplant, then radiation
to the primary tumor bed, followed by anti-GD2 immunotherapy and cis retinoic acid. This
results in a less than 60% disease free survival for high-risk NB, a survival rate that
still greatly needs improvement. Two areas in which improvements can be made include: 1)
to improve response rate to induction chemotherapy and 2) to improve EFS by improving
maintenance therapy to prevent relapse.

We hypothesize that the addition of anti-GD2 therapy to induction chemotherapy will
result in improved end of induction responses and improved survival.

Eligibility

1. Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Subjects with the following disease stages at diagnosis are eligible, if they meet the other specified criteria: a) Subjects with newly diagnosed neuroblastoma with International Neuroblastoma Staging 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-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features. b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: i. MYCN amplification (> 4-fold increase in MYCN signals as compared to 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 MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.
2. Subjects must be age = 21 years at initial diagnosis
3. Subjects must be >12 months of age at enrollment
4. Ability to tolerate Peripheral blood stem cell (PBSC) collection: No known contraindication to PBSC collection. Examples of contraindications would include a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.
5. Adequate Cardiac Function Defined As:
6. Shortening fraction of = 27% by echocardiogram, or
7. Ejection fraction of = 50% by radionuclide evaluation or echocardiogram.
8. Adequate liver function must be demonstrated, defined as:
9. Total bilirubin = 1.5 x upper limit of normal (ULN) for age AND
10. ALT (SGPT) < 5 x upper limit of normal (ULN) for age
11. Subjects must have adequate renal function defined as a serum creatinine based on age/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
12. A negative serum pregnancy test is required for female participants of childbearing potential (=13 years of age or after onset of menses)
13. Both male and female post-pubertal study subjects must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) from the time of informed consent until 6 months after study treatment discontinuation. Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence.
14. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Treatment Sites in Georgia