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N99-02: Melphalan and Buthionine Sulfoximine (BSO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00005835
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : August 30, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium

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:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : August 2001
Actual Primary Completion Date : December 2014
Actual Study Completion Date : April 2016

Intervention Details:
  • 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

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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. ]
    Collection of blood samples for PK studies is optional and not required for study entry.

  2. 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. ]
  3. 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. ]
    Collection of blood samples for biologic studies is optional and not required for study entry.

  4. 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. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00005835

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United States, California
Childrens Hospital Los Angeles
Los Angeles, California, United States, 90027-0700
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, Illinois
University of Chicago Comer Children's Hospital
Chicago, Illinois, United States, 60637
United States, Massachusetts
Childrens Hospital Boston, Dana-Farber Cancer Institute.
Boston, Massachusetts, United States, 02115
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
United States, Texas
Cook Children's Medical Center - Fort Worth
Fort Worth, Texas, United States, 76104
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
National Cancer Institute (NCI)
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Study Chair: Samuel Volchenboum, MD Comer Children's Hospital, University of Chicago

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Responsible Party: New Approaches to Neuroblastoma Therapy Consortium Identifier: NCT00005835    
Other Study ID Numbers: CDR0000067849
P01CA081403 ( U.S. NIH Grant/Contract )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: August 30, 2016
Last Verified: June 2016
Keywords provided by New Approaches to Neuroblastoma Therapy Consortium:
regional neuroblastoma
disseminated neuroblastoma
recurrent neuroblastoma
localized unresectable neuroblastoma
Additional relevant MeSH terms:
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Buthionine Sulfoximine
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Antimetabolites, Antineoplastic
Enzyme Inhibitors
Radiation-Protective Agents
Protective Agents