Pediatric Precision Laboratory Advanced Neuroblastoma Therapy

• Ceritinib (Drug), also known as Zykadia: One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• dasatinib (Drug), also known as Sprycel: One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• sorafenib (Drug), also known as Nexavar: One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• vorinostat (Drug), also known as ZOLINZA: One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• DFMO (Drug), also known as Eflornithine, α-difluoromethylornithine: DFMO will be given to Arm B during immunotherapy and then for 2 years as maintenance to all subjects completing immunotherapy.

Primary outcomes

• Number of days from start of therapy to date of first relapse [Up to 8 years]: To measure the response of treatments chosen based on: • Event free survival (EFS)
• Number of subjects that have a targeted agent chosen for treatment. [2 years]: At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: 1. Subject has a targeted agent identified 2. Receives 75% of dosing of medications while on study protocol during cycles 3-6 3. Subject is not removed from study due to targeted agent drug related toxicity.
• Number of subjects that receive 75% of dosing of medications while on study protocol during cycles 3-6. [2 years]: At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: 1. Subject has a targeted agent identified 2. Receives 75% of dosing of medications while on study protocol during cycles 3-6 3. Subject is not removed from study due to targeted agent drug related toxicity.

Secondary outcomes

• Number of days that subjects remain alive [3 years plus 5 years follow up]: To measure the response of treatments chosen based on: * Overall response rate (ORR) after induction therapy * Overall survival (OS)
• Overall Response Rate (ORR) of Participants by the presence of radiologically assessable disease by cross-sectional CT or MRI imaging and/or by MIBG or PET scans. [Up to 8 years]: To measure the response of treatments chosen based on: • Overall response rate (ORR) after induction therapy
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [3 years]: To compare toxicity effects of difluoromethylornithine (DFMO) in combination with anti-GD2 immunotherapy and isotretinoin versus anti-GD2 immunotherapy and isotretinoin alone.
• Amount of pain medicine required by Arm A versus Arm B [3 years]: To compare level of pain medicine needed during immunotherapy in patients receiving difluoromethylornithine (DFMO) in combination with anti-GD2 immunotherapy and Isotretinoin versus those receiving anti-GD2 immunotherapy and isotretinoin alone.
• Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0. [1 year]: At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: 1. Subject has a targeted agent identified 2. Receives 75% of dosing of medications while on study protocol during cycles 3-6 3. Subject is not removed from study due to targeted agent drug related toxicity.

Sex: All, ages: any to 22 Years

Part A- CLOSED:

1. Diagnosis: Participants 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. Participants with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

   a) Participants with newly diagnosed neuroblastoma with 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) Participants 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) Participants 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. Participants must be age ≤ 21 years at initial diagnosis
3. Participants must not 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.
4. Specimens will be obtained only in a non-significant risk manner and not solely for the purpose of investigational testing.
5. Ability to tolerate 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.

   Part A and B both- Part A CLOSED, Part B- OPEN:
6. Adequate Cardiac Function Defined As:

   1. Shortening fraction of ≥ 27% by echocardiogram, or
   2. Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.
7. Adequate liver function must be demonstrated, defined as:

   c. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND d. ALT (SGPT) < 10 x upper limit of normal (ULN) for age
8. ⦁ For participants < 17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units of mL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Bedside Schwartz equation is: \[(0.413) X (Height in cm)\] / SCr

   ⦁ For participants ≥17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Cockcroft and Gault formula (in units of mL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Cockcroft and Gault formula is: \[(140-age) x (Wt in kg) x (0.85 if female)\] / (72 x SCr)
9. A negative serum pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses)
10. Post-pubertal study participants 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 (and assent, as applicable) 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.
11. Informed Consent: All participants and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

    Part B- OPEN:
12. All patients must have a pathologically confirmed diagnosis of neuroblastoma, be age ≤ 21 years at initial diagnosis, and classified as high risk by the criteria used by COG or SIOPEN at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.
13. Previous Therapy- participants must fit into one of the strata categories listed in section 10.5 to be eligible to enroll on Part B of this study.
14. Pre-enrollment tumor survey:

    Prior to enrollment on Part B, a determination of mandatory disease staging must be performed. Tumor imaging studies including CT or MRI, MIBG or PET, and VMA/HVA (PET scan should be done for patients with prior disease that was MIBG non-avid). Bone marrow aspirates and biopsies are required.

    This disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before first dose of study drug.
15. Timing- Enrollment to occur prior to Day + 120 post-transplant, preferably when the participant is within 28 days after completing local radiation therapy (if given).

Exclusion Criteria (Part A and B)

1. Participants who are 12-18 months of age with INSS Stage 4 and all stage 3 participants with favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible.
2. Lactating females are not eligible unless they have agreed not to breastfeed their infants.
3. Participants receiving any investigational drug concurrently.
4. Participants 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 participant's ability to sign or the legal guardian's ability to sign the informed consent, and participant's ability to cooperate and participate in the study

• Giselle Sholler, MD, Study chair, Beat Childhood Cancer