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 recurrent or refractoryneuroblastoma.

Condition	Treatment or Intervention	Phase
regional neuroblastoma disseminated neuroblastoma recurrent neuroblastoma localized unresectable neuroblastoma	Drug: buthionine sulfoximine  Drug: filgrastim  Drug: melphalan  Procedure: autologous bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: peripheral blood stem cell transplantation	Phase I

Further Study Details: 

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 recurrent or refractory 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 continuously for 72.5 hours 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 every 2 months for the next 4 months if there is a complete and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy.

PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 2-3 years.

Ages Eligible for Study:  up to  18 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of high-risk neuroblastoma confirmed by histology and/or tumor cells in bone marrow with elevated urinary catecholamine metabolites
• Refractory to conventional therapy or other therapies of higher priority
• Disease progression with failure to respond or disease progression after standard salvage therapy OR
• Underwent prior hematopoietic stem cell transplantation at least 6 months ago with failure to respond or disease progression after standard salvage therapy
• Availability of at least 1.5 x 10
• CD34-positive purged/unpurged autologous peripheral blood stem cells per kg of body weight OR
• Availability of at least 1 x 10^8 purged autologous mononuclear bone marrow cells per kg of body weight
• 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 3-iodobenzylguanidine scan

PATIENT CHARACTERISTICS: Age:

• Over 9 months to 18 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 at least 80 mL/min
• Creatinine normal
• No history of grade 2 or greater creatinine elevation during prior antibiotic therapy within the past 6 months

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
• 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
• More than 6 months since prior radiotherapy to any of the following fields:
• Mandible (no greater than 1,000 cGy)
• Mantle and Y ports
• At least 2 weeks since prior radiotherapy to all other sites
• Prior abdominal radiotherapy allowed if at least 1 entire kidney has not been exposed to therapeutic radiotherapy of any form
• Prior diagnostic radiotherapy allowed
• No prior radiotherapy to the brain (including craniospinal, whole brain, or to a craniofacial metastasis except the mandible)
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• Recovered from any prior therapy
• No concurrent antiretroviral medications for HIV-positive patients
• No acetaminophen, antibiotics (including cephalosporins), antifungals, or antivirals for at least 1 week before, during, or for at least 2 weeks after buthionine sulfoximine infusion

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-6016,  United States
      Lucile Packard Children's Hospital at Stanford University Medical Center, Palo Alto,  California,  94304,  United States
      University of California-San Francisco School of Medicine, San Francisco,  California,  94143-0410,  United States
Georgia
      AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus, Atlanta,  Georgia,  30322,  United States
Illinois
      Children's Memorial Hospital - Chicago, Chicago,  Illinois,  60614,  United States
Indiana
      James Whitcomb Riley Hospital for Children, Indianapolis,  Indiana,  46202-5225,  United States
Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States
Massachusetts
      Children's Hospital Boston, Boston,  Massachusetts,  02115,  United States
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
Michigan
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0942,  United States
Ohio
      Cincinnati Children's Hospital Medical Center, Cincinnati,  Ohio,  45229-3039,  United States
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
Texas
      Texas Children's Cancer Center, Houston,  Texas,  77030-2399,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-6164,  United States

Study chairs or principal investigators

Clarke Anderson,  Study Chair,  Children's Hospital Los Angeles   

Study ID Numbers:  CDR0000067849; NANT-99-02; CHLA-LA-NANT-99-02; NCI-68
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  June 2, 2000
ClinicalTrials.gov Identifier:  NCT00005835
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08