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Melphalan and Buthionine Sulfoximine Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Children With Resistant or Recurrent Neuroblastoma
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), November 2008
First Received: June 2, 2000   Last Updated: February 7, 2009   History of Changes
Sponsored by: New Approaches to Neuroblastoma Therapy Consortium
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00005835
  Purpose

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 Intervention Phase
Neuroblastoma
Biological: filgrastim
Drug: buthionine sulfoximine
Drug: melphalan
Procedure: autologous bone marrow transplantation
Procedure: peripheral blood stem cell transplantation
Phase I

MedlinePlus related topics: Bone Marrow Transplantation Cancer Neuroblastoma
Drug Information available for: Filgrastim Melphalan Sarcolysin Melphalan hydrochloride Buthionine sulfoximine
U.S. FDA Resources
Study Type: Interventional
Study Design: 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)

Further study details as provided by National Cancer Institute (NCI):

Estimated Enrollment: 30
Study Start Date: August 2001
Estimated Primary Completion Date: November 2001 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   up to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of high-risk neuroblastoma confirmed by histology and/or tumor cells in bone marrow with elevated urinary catecholamine metabolites
  • Meets 1 of the following response status criteria:

    • Current or previous progressive disease
    • Mixed or no response following completion of minimum of 4 courses of induction therapy
  • Meets 1 of the following criteria:

    • Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
    • Metaiodobenzylguanidine (MIBG) scan with uptake at a minimum of one site
    • Bone marrow disease documented by standard morphology of bilateral bone marrow aspirate and biopsy specimens

      • Documentation by positive immunocytology is not sufficient
    • Biopsy of a lesion seen on bone scan that is non-avid for MIBG and that demonstrates viable neuroblastoma
  • Meets 1 of the following criteria for harvested autologous stem cells:

    • Availability of at least 1.5 x 10^6 CD34-positive unpurged autologous peripheral blood stem cells per kg of body weight*
    • Availability of at least 1.0 x 10^6 viable CD34-positive purged autologous peripheral blood stem cells per kg of body weight*

      • A backup source of stem cells is required if there are < 1.5 x 10^6 CD34-positive viable cells/kg available for infusion
    • Availability of at least 1 x 10^8 purged autologous mononuclear bone marrow cells per kg of body weight* NOTE: *Product to be infused must have 0 tumor cells by immunocytology
  • No history of intraparenchymal brain lesion
  • No concurrent intraparenchymal brain lesion or meningeal/parameningeal soft tissue mass extending directly into the cranial cavity by CT, MRI, or metaiodobenzylguanidine scan

PATIENT CHARACTERISTICS:

Age:

  • Over 9 months to 30 years

Performance status:

  • ECOG or Zubrod 0-1

Life expectancy:

  • At least 2 months

Hematopoietic:

  • Absolute neutrophil count at least 500/mm^3
  • Platelet count at least 20,000/mm^3 (transfusion allowed)
  • Hemoglobin at least 10 g/dL (transfusion allowed)

Hepatic:

  • Bilirubin normal
  • AST and ALT no greater than 2.5 times normal
  • No active hepatitis if HIV positive

Renal:

  • Glomerular filtration rate or creatinine clearance ≥ 100 mL/min
  • Creatinine ≤ 1.5 times normal

Cardiovascular:

  • Ejection fraction at least 55% by echocardiogram or MUGA scan OR
  • Fractional shortening at least 30% by echocardiogram

Pulmonary:

  • No dyspnea at rest or exercise intolerance
  • No active pneumonia if HIV positive

Neurologic:

  • No grade 1 or greater neurological function abnormality except grade 1 irritability, headache, dizziness, insomnia, or somnolence (if due to narcotic analgesics)
  • No history of seizures

Other:

  • No other active health problems if HIV positive
  • No concurrent neoplastic or nonneoplastic disease of any major organ system that would preclude study participation
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • See Disease Characteristics
  • At least 3 weeks since prior biologic therapy and recovered

Chemotherapy:

  • At least 3 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered
  • No other concurrent anticancer chemotherapy

Endocrine therapy:

  • Not specified

Radiotherapy:

  • Recovered from prior radiotherapy
  • Prior diagnostic radiotherapy allowed
  • More than 6 months since prior radiotherapy to mantle and Y ports
  • More than 3 months since prior therapeutic metaiodobenzylguanidine (^131I-MIBG) and no more than 20 mCl/kg total dose received
  • At least 2 weeks since prior radiotherapy to all other sites
  • More than 6 months since prior radiotherapy to kidneys, liver, heart, skull, or face

    • No more than 25% of the liver can have received > 1800 cGy
    • No more than 20% of one of the kidneys can have received > 1200 cGy
    • No more than a 10 cc volume of the brain can have received > 1000 cGy
  • No prior total body irradiation
  • No prior total cranial or craniospinal radiotherapy
  • No concurrent radiotherapy

Surgery:

  • Not specified

Other:

  • Recovered from any prior therapy
  • At least 7 days since prior antibiotics, antifungals, or antivirals
  • No acetaminophen or cephalosporin antibiotics for at least 7 days before, during, and until at least 2 weeks after buthionine sulfoximine infusion
  • No prophylactic antimicrobials (i.e., nystatin or sulfamethoxazole/trimethoprim) for at least 7 days before, during, and until at least 7 days after buthionine sulfoximine infusion
  • No concurrent antiretroviral medications for HIV-positive patients
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00005835

Locations
United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027-0700
Contact: Judith G. Villablanca, MD     323-361-5654     jvillablanca@chla.usc.edu    
Lucile Packard Children's Hospital at Stanford University Medical Center Recruiting
Palo Alto, California, United States, 94304
Contact: Clare Twist, MD     650-723-5535        
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94143
Contact: Katherine K. Matthay, MD     415-476-3831        
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Recruiting
Atlanta, Georgia, United States, 30322
Contact: Howard M. Katzenstein, MD     404-785-0853        
United States, Illinois
University of Chicago Comer Children's Hospital Recruiting
Chicago, Illinois, United States, 60637
Contact: Susan L. Cohn, MD     773-703-2571     scohn@peds.bsd.uchicago.edu    
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suzanne Shusterman, MD     617-632-4901     suzanne_shusterman@dfci.harvard.edu    
United States, Michigan
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Gregory Yanik, MD     734-936-8785     gyanik@umich.edu    
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: John P. Perentesis, MD     513-636-6090     john.perentesis@chmcc.org    
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104-4318
Contact: John M. Maris, MD     215-590-5242     maris@chop.edu    
United States, Washington
Children's Hospital and Regional Medical Center - Seattle Recruiting
Seattle, Washington, United States, 98105
Contact: Julie R. Park, MD     206-987-2106        
United States, Wisconsin
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Recruiting
Madison, Wisconsin, United States, 53792-6164
Contact: Paul M. Sondel, MD, PhD     608-263-9069     pmsondel@humonc.wisc.edu    
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
Investigators
Study Chair: Judith G. Villablanca, MD Children's Hospital Los Angeles
  More Information

Additional Information:
No publications provided

Study ID Numbers: CDR0000067849, NANT-99-02, CHLA-LA-NANT-99-02, CHLA-CCI-00.020
Study First Received: June 2, 2000
Last Updated: February 7, 2009
ClinicalTrials.gov Identifier: NCT00005835     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
regional neuroblastoma
disseminated neuroblastoma
recurrent neuroblastoma
localized unresectable neuroblastoma

Study placed in the following topic categories:
Antimetabolites
Melphalan
Radiation-Protective Agents
Neuroectodermal Tumors, Primitive
Immunologic Factors
Buthionine Sulfoximine
Immunosuppressive Agents
Neuroblastoma
Recurrence
Neuroectodermal Tumors
Radiation-Sensitizing Agents
Neoplasms, Germ Cell and Embryonal
Neuroepithelioma
Antineoplastic Agents, Alkylating
Alkylating Agents
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:
Antimetabolites
Melphalan
Radiation-Protective Agents
Neuroectodermal Tumors, Primitive
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Neoplasms, Nerve Tissue
Physiological Effects of Drugs
Neuroblastoma
Neoplasms, Germ Cell and Embryonal
Therapeutic Uses
Alkylating Agents
Neoplasms by Histologic Type
Buthionine Sulfoximine
Enzyme Inhibitors
Protective Agents
Immunosuppressive Agents
Pharmacologic Actions
Neuroectodermal Tumors
Neoplasms
Radiation-Sensitizing Agents
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Neoplasms, Neuroepithelial
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on May 07, 2009