A Study of N9 Chemotherapy in Children With Neuroblastoma

• Cyclophosphamide (Drug), also known as Cytoxan: Administration of CTV - cycles 1 and 4 Days 1 \& 2: Cyclophosphamide 70 mg/kg/day (2100 mg/m2/day for patients >10 years old), IV over 6 hrs. Mesna 70 mg/kg (2100 mg/m2/day for patients >10 years old) , by 24-hr IV infusion, starting with the cyclophosphamide infusion. Days 1-4: Topotecan 2 mg/m2/day, IV over 30 minutes. Day 1: Vincristine 0.067 mg/kg (or 2 mg/m2, whichever is less) by IV piggyback; maximum dose is 2 mg. ******* Administration of CDV - cycle 3 Days 1 \& 2: Cyclophosphamide 70 mg/kg/day ((2100 mg/m2/day for patients >10 years old), IV over 6 hrs. Mesna 70 mg/kg ((2100 mg/m2/day for patients >10 years old), by 24-hr IV infusion, starting with the cyclophosphamide infusion. Days 1-3: Doxorubicin 25 mg/m2/day, by 24-hr IV infusion (total dose over 72 hr is 75 mg/m2). Days 1-3: Vincristine 0.67 mg/m2/day or 0.022 mg/kg/day (whichever is less), by 24-hr IV infusion (total dose over 72 hr is 2 mg/m2 or 0.067 mg/kg); maximum dose is 0.67 mg/day, or 2mg over 72 hr.
• Topotecan (Drug), also known as Hycamtin: Administration of CTV - cycles 1 and 4 Days 1 \& 2: Cyclophosphamide 70 mg/kg/day (2100 mg/m2/day for patients >10 years old), IV over 6 hrs. Mesna 70 mg/kg (2100 mg/m2/day for patients >10 years old) , by 24-hr IV infusion, starting with the cyclophosphamide infusion. Days 1-4: Topotecan 2 mg/m2/day, IV over 30 minutes. Day 1: Vincristine 0.067 mg/kg (or 2 mg/m2, whichever is less) by IV piggyback; maximum dose is 2 mg.
• Vincristine (Drug), also known as Oncovin: Administration of CTV - cycles 1 and 4 Days 1 \& 2: Cyclophosphamide 70 mg/kg/day (2100 mg/m2/day for patients >10 years old), IV over 6 hrs. Mesna 70 mg/kg (2100 mg/m2/day for patients >10 years old) , by 24-hr IV infusion, starting with the cyclophosphamide infusion. Days 1-4: Topotecan 2 mg/m2/day, IV over 30 minutes. Day 1: Vincristine 0.067 mg/kg (or 2 mg/m2, whichever is less) by IV piggyback; maximum dose is 2 mg.
• Doxorubicin (Drug), also known as Adriamycin: Administration of CDV - cycle 3 Days 1 \& 2: Cyclophosphamide 70 mg/kg/day ((2100 mg/m2/day for patients >10 years old), IV over 6 hrs. Mesna 70 mg/kg ((2100 mg/m2/day for patients >10 years old), by 24-hr IV infusion, starting with the cyclophosphamide infusion. Days 1-3: Doxorubicin 25 mg/m2/day, by 24-hr IV infusion (total dose over 72 hr is 75 mg/m2). Days 1-3: Vincristine 0.67 mg/m2/day or 0.022 mg/kg/day (whichever is less), by 24-hr IV infusion (total dose over 72 hr is 2 mg/m2 or 0.067 mg/kg); maximum dose is 0.67 mg/day, or 2mg over 72 hr.
• Ifosfamide (Drug), also known as Isophosphamide: Administration of ICE - cycle 2 Days 1-5: Ifosfamide 1500 mg/m2/day (50 mg/kg/day if weight is <10 kg), IV over 6 hrs. Mesna 1500 mg/m2/day, by 24-hr IV infusion, starting with the ifosfamide infusion. Days 1-2: Carboplatin 400 mg/m2/day (13.3 mg/kg/day if weight is <10 kg), IV over 1 hr. Days 1-5: Etoposide 100 mg/m2/day (3.3. mg/kg/day if weight is <10 kg), IV over 2 hrs.
• Etoposide (Drug), also known as VePesid, Etopophos: Administration of ICE - cycle 2 Days 1-5: Ifosfamide 1500 mg/m2/day (50 mg/kg/day if weight is <10 kg), IV over 6 hrs. Mesna 1500 mg/m2/day, by 24-hr IV infusion, starting with the ifosfamide infusion. Days 1-2: Carboplatin 400 mg/m2/day (13.3 mg/kg/day if weight is <10 kg), IV over 1 hr. Days 1-5: Etoposide 100 mg/m2/day (3.3. mg/kg/day if weight is <10 kg), IV over 2 hrs.
• Carboplatin (Drug), also known as Paraplatin: Administration of ICE - cycle 2 Days 1-5: Ifosfamide 1500 mg/m2/day (50 mg/kg/day if weight is <10 kg), IV over 6 hrs. Mesna 1500 mg/m2/day, by 24-hr IV infusion, starting with the ifosfamide infusion. Days 1-2: Carboplatin 400 mg/m2/day (13.3 mg/kg/day if weight is <10 kg), IV over 1 hr. Days 1-5: Etoposide 100 mg/m2/day (3.3. mg/kg/day if weight is <10 kg), IV over 2 hrs.
• Mesna (Drug), also known as Mesnex: Administration of CTV - cycles 1 and 4 Mesna 70 mg/kg (2100 mg/m2/day for patients >10 years old) , by 24-hr IV infusion, starting with the cyclophosphamide infusion. Administration of ICE - cycle 2 Mesna 1500 mg/m2/day, by 24-hr IV infusion, starting with the ifosfamide infusion. Administration of CDV - cycle 3 Mesna 70 mg/kg ((2100 mg/m2/day for patients >10 years old), by 24-hr IV infusion, starting with the cyclophosphamide infusion.

Primary outcomes

• Assess safety of the N9 regimen in participants with HR-NB through toxicity assessment [16 weeks]: Adverse events will be graded using Common Toxicity Criteria Version 5.0 developed by the National Cancer Institute of the USA, events of all grades will be tabulated, for non-hematologic effects and hematologic effects on the patients in the safety set. The timing of cycles will also be described to assess any delay due to toxicity

Sex: All, ages: 1 Year to 19 Years

Inclusion Criteria:

* Diagnosis of NB as defined by histopathology (confirmed by the MSK Department of Pathology), BM metastases plus high urine catecholamine levels, or positivity in MIBG scan.
* HR-NB, defined as MYCN-amplified stage 2/3/4/4S at any age and stage 4 in patients >18 months old.
* No more than one prior cycle of chemotherapy.
* Age <19 years old.
* Signed informed consent indicating awareness of the investigational nature of this treatment.

Exclusion Criteria:

* Severe dysfunction of major organs, i.e., renal, cardiac, hepatic, neurologic, pulmonary, hematologic, or gastrointestinal toxicity ≥ grade 3.
* Inability to comply with protocol requirements.
* Pregnancy is not an issue because all patients will be pre-adolescents.

• Brian Kushner, MD, Principal investigator, Memorial Sloan Kettering Cancer Center