Clinical trial NCT00005835: N99-02: Melphalan and Buthionine Sulfoximine
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuroblastoma
Keywords: regional neuroblastoma
disseminated neuroblastoma
recurrent neuroblastoma
localized unresectable neuroblastoma
Lead sponsor: New Approaches to Neuroblastoma Therapy Consortium
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 31
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: Within 4 weeks of completion of BSO/L-PAM therapy
Secondary outcomes:
measure: To determine the pharmacokinetics (PK) of BSO and L-PAM in pediatric patients.
timeFrame: 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.
measure: To determine the response rate of recurrent high risk neuroblastoma to BSO/LPAM within the confines of a phase I study.
timeFrame: 84 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.
measure: To determine the glutathione content of peripheral blood leucocytes in patients receiving BSO and L-PAM.
timeFrame: 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.
measure: To determine the number of days to ANC =/> 500 for three days and platelets =/> 20,000 for three days (without transfusion) for this regimen.
timeFrame: Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago Comer Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Childrens Hospital Boston, Dana-Farber Cancer Institute.
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Comer Children's Hospital, University of Chicago
name: Samuel Volchenboum, MD
role: STUDY_CHAIR
References:
citation: 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.