BSO: N99-02: Melphalan and Buthionine Sulfoximine

Sponsor

New Approaches to Neuroblastoma Therapy Consortium (Other)

Overall Status

Completed

CT.gov ID

NCT00005835

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

176

Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Drug: buthionine sulfoximine Drug: melphalan Procedure: Peripheral blood stem cell infusion Other: Filgrastim	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2001

Actual Primary Completion Date :

Dec 1, 2014

Actual Study Completion Date :

Apr 1, 2016

Outcome Measures

Primary Outcome Measures

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

To determine the pharmacokinetics (PK) of BSO and L-PAM in pediatric patients. [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.]
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. [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. [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.]
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. [Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027-0700
2	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94143
3	University of Chicago Comer Children's Hospital	Chicago	Illinois	United States	60637
4	Childrens Hospital Boston, Dana-Farber Cancer Institute.	Boston	Massachusetts	United States	02115
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4318
7	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
8	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105
9	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8