N99-02: Melphalan and Buthionine Sulfoximine

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow or peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children who have resistant or recurrent neuroblastoma.

Detailed Description
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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.

Official Title
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Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) Autologous Stem Cell Support for Resistant or Recurrent High-Risk Neuroblastoma (IND 69-112)

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: buthionine sulfoximine
* Drug: melphalan
* Procedure: Peripheral blood stem cell infusion
* Other: Filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have relapsed neuroblastoma and must have exhausted all other options for treatment before they can be considered for treatment on this study. Relapsed patients who are greater than 6 months since having a stem cell transplant can enter on this study. Patients must have stem cells collected and stored before starting treatment. Patients must have a double lumen central venous line in place. Patients must have adequate kidney and liver function measured by blood tests and test of renal function (creatinine clearance or glomerular filtration rate (GFR)). Patients must have normal heart and lung function measured by lack of physical evidence or clinical history of difficulties breathing and tests of cardiac function (Echocardiogram or MUGA evaluation). Patients must have an essentially normal neurological exam. Patients must have one entire kidney that has not had any radiation at treatment doses. (Xrays and scans are ok). Patients must have recovered from the effects of any prior treatment for their tumor. Exclusion Criteria: They have had any radiation therapy to the brain. They have known history of or current tumor found in the brain or surrounding tissues. They have a history of seizures. They have a history of changes in a test of kidney function with antibiotic use in the 6 months immediately before entering on this study.

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Group<br> | Drug: buthionine sulfoximine<br>* 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.<br>* Other names: BSO;Drug: melphalan<br>* 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.<br>* Other names: L-PAM;Procedure: Peripheral blood stem cell infusion<br>* 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.<br>* Other names: ABMT;Other: Filgrastim<br>* 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.<br>* Other names: G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | Within 4 weeks of completion of BSO/L-PAM therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the pharmacokinetics (PK) of BSO and L-PAM in pediatric patients. | Collection of blood samples for PK studies is optional and not required for study entry. | 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. | 
| To determine the response rate of recurrent high risk neuroblastoma to BSO/LPAM within the confines of a phase I study. |  | 84 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion. | 
| To determine the glutathione content of peripheral blood leucocytes in patients receiving BSO and L-PAM. | Collection of blood samples for biologic studies is optional and not required for study entry. | 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. | 
| To determine the number of days to ANC =/> 500 for three days and platelets =/> 20,000 for three days (without transfusion) for this regimen. |  | Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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regional neuroblastoma, disseminated neuroblastoma, recurrent neuroblastoma, localized unresectable neuroblastoma