N99-02: Melphalan and Buthionine Sulfoximine

NCT00005835 | Completed Phase 1 DMC

• 3 other identifiers: CDR0000067849P01CA081403NANT-99-02
• Study Type: interventional
• Target: 31
• Locations: 2 countries
• Sites: 9

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.

Conditions

Neuroblastoma

Keywords

regional neuroblastoma; disseminated neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma

Outcome Measures

Primary Outcomes (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.

  Within 4 weeks of completion of BSO/L-PAM therapy

Secondary Outcomes (4)

• To determine the pharmacokinetics (PK) of BSO and L-PAM in pediatric patients.

  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.

• To determine the response rate of recurrent high risk neuroblastoma to BSO/LPAM within the confines of a phase I study.

  84 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.

• To determine the glutathione content of peripheral blood leucocytes in patients receiving BSO and L-PAM.

  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.

• To determine the number of days to ANC =/> 500 for three days and platelets =/> 20,000 for three days (without transfusion) for this regimen.

  Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.

Study Arms (1)

Single Group

EXPERIMENTAL

Drug: buthionine sulfoximine; Drug: melphalan; Procedure: Peripheral blood stem cell infusion; Other: Filgrastim

Interventions

buthionine sulfoximine DRUG

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.

Also known as: BSO

Single Group

melphalan DRUG

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.

Also known as: L-PAM

Single Group

Peripheral blood stem cell infusion PROCEDURE

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.

Also known as: PBSCT, Autologous Bone marrow Transplant, ABMT

Single Group

Filgrastim OTHER

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.

Also known as: G-CSF

Single Group

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• New Approaches to Neuroblastoma Therapy Consortium: lead
• National Cancer Institute (NCI): collaborator

Study Sites (9)

Childrens Hospital Los Angeles

Los Angeles, California, 90027-0700, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

University of Chicago Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

Childrens Hospital Boston, Dana-Farber Cancer Institute.

Boston, Massachusetts, 02115, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

Cook Children's Medical Center - Fort Worth

Fort Worth, Texas, 76104, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• 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.

  PMID: 27092812 BACKGROUND

MeSH Terms

Conditions

Neuroblastoma

Interventions

Buthionine Sulfoximine; Melphalan; Filgrastim; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Methionine Sulfoximine; Methionine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Proteins; Biological Factors

Study Officials

• Samuel Volchenboum, MD

  Comer Children's Hospital, University of Chicago

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2000
• First Posted: January 27, 2003
• Study Start: August 1, 2001
• Primary Completion: December 1, 2014
• Study Completion: April 1, 2016
• Last Updated: April 10, 2023

Record last verified: 2023-04

Locations

CA (1); US (8)