Study Results
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Basic Information
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COMPLETED
PHASE1
31 participants
INTERVENTIONAL
2001-08-31
2016-04-30
Brief Summary
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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.
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Detailed Description
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* 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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Single Group
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.
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.
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.
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.
Interventions
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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.
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.
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.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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.
30 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
New Approaches to Neuroblastoma Therapy Consortium
OTHER
Responsible Party
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Principal Investigators
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Samuel Volchenboum, MD
Role: STUDY_CHAIR
Comer Children's Hospital, University of Chicago
Locations
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Childrens Hospital Los Angeles
Los Angeles, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States
University of Chicago Comer Children's Hospital
Chicago, Illinois, United States
Childrens Hospital Boston, Dana-Farber Cancer Institute.
Boston, Massachusetts, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Cook Children's Medical Center - Fort Worth
Fort Worth, Texas, United States
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States
Hospital for Sick Children
Toronto, Ontario, Canada
Countries
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References
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Villablanca JG, Volchenboum SL, Cho H, Kang MH, Cohn SL, Anderson CP, Marachelian A, Groshen S, Tsao-Wei D, Matthay KK, Maris JM, Hasenauer CE, Czarnecki S, Lai H, Goodarzian F, Shimada H, Reynolds CP. A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma. Pediatr Blood Cancer. 2016 Aug;63(8):1349-56. doi: 10.1002/pbc.25994. Epub 2016 Apr 19.
Other Identifiers
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NANT-99-02
Identifier Type: -
Identifier Source: secondary_id
CDR0000067849
Identifier Type: -
Identifier Source: org_study_id
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