Naxitamab Added to Induction for Newly Diagnosed High-Risk Neuroblastoma

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. Subjects with an ALK mutation or amplification will have ceritinib added to their treatment regimen as soon as results are available. We hypothesize that the addition of anti-GD2 therapy to induction chemotherapy will result in improved end of induction responses and improved survival.

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.

Subjects with an activating ALK mutation or ALK amplification will have ceritinib added to their treatment regimen as soon as results are available.

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.

Inclusion Criteria:

• 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.

• 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 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.

• 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 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

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

• 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) are not eligible.

• Subjects who have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.

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

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

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

• Subjects receiving any investigational drug concurrently.

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

• Subjects with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of investigational medicinal products (IMPs) or to significantly increase the severity of the toxicities experienced from trial treatment.