• To determine the maximum tolerated dose(MTD) and the toxicities of Melphalan (L-PAM) escalated in the presence of Buthionine sulphoxamine (BSO) and followed by autologous stem cells rescue for pediatric patients with high-risk neuroblastoma. [ Time Frame: Within 4 weeks of completion of BSO/L-PAM therapy ] [ Designated as safety issue: Yes ]
  

• To determine the pharmacokinetics (PK) of BSO and L-PAM in pediatric patients. [ Time Frame: For BSO: just before start of therapy to 8 hours post end of 72 infusion. For L-PAM : just before start of 2nd dose to 4 hours post. ] [ Designated as safety issue: Yes ]
  Collection of blood samples for PK studies is optional and not required for study entry.
  
  
• To determine the response rate of recurrent high risk neuroblastoma to BSO/LPAM within the confines of a phase I study. [ Time Frame: 84 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion. ] [ Designated as safety issue: No ]
  
• To determine the glutathione content of peripheral blood leucocytes in patients receiving BSO and L-PAM. [ Time Frame: For BSO: just before start of therapy to 8 hours post end of 72 infusion. For L-PAM : just before start of 2nd dose to 4 hours post. ] [ Designated as safety issue: No ]
  Collection of blood samples for biologic studies is optional and not required for study entry.
  
  
• To determine the number of days to ANC =/> 500 for three days and platelets =/> 20,000 for three days (without transfusion) for this regimen. [ Time Frame: Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion. ] [ Designated as safety issue: Yes ]
  

Drug: buthionine sulfoximine
Dose fixed at a bolus of 3 gm/M2 given over 30 minutes followed by a continuous infusion of 1 gm/M2/hour for 72 hours (total 72.5 hours).Total daily infusion dose (minus the initial bolus)will be 24 gm/m2/day.
Other Name: BSO
Drug: melphalan
The dose level of melphalan will be assigned at study entry onto protocol. There will be 6 dose levels ranging from 20mg/m2/day x 2 days (dose level 1a) to 62.5 mg/m2/day x 2 days (dose level 6a). The starting dose level will be 1a, with a decrease to level 0a (15mg/m2/day x2 days) if there is unacceptable toxicity.
Other Name: L-PAM
Procedure: Peripheral blood stem cell infusion
Stem cells will be infused intravenously on day 0 , 24 hours after BSO continuous infusion is completed.Infused within 1.5 hours of thawing via a central venous catheter over 15-30 minutes.
Other Names:
• PBSCT
• Autologous Bone marrow Transplant
• ABMT
Other: Filgrastim
5 microgram/kg/day , subcutaneous or intravenous, given daily beginning day 0. First dose to begin 4 hours after completion of stem cell infusion and then to continue till ANC >/= 1500 mm3 for three consecutive days.
Other Name: G-CSF

OBJECTIVES:

• Determine the maximum tolerated dose of melphalan when combined with buthionine sulfoximine and followed by autologous bone marrow or peripheral blood stem cell support in children with resistant or recurrent high-risk neuroblastoma.
• Assess the toxic effects of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine the response rate of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of melphalan.

Patients receive buthionine sulfoximine IV as a bolus over 30 minutes followed by a 72-hour continuous infusion beginning on day -4; melphalan IV over 15 minutes on days -3 and -2; autologous peripheral blood stem cells or bone marrow IV over 15-30 minutes on day 0; and filgrastim (G-CSF) subcutaneously or IV once daily beginning on day 0 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 84 days and then 2 months later if there is a complete and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy. All patients are followed for life for any delayed toxic effects to protocol therapy and secondary malignancies.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 2-3 years.