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Completed

NCT Number: NCT00005835

N99-02: Melphalan and Buthionine Sulfoximine

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.

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Key information

Conditions

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

Age range

Up to 30 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Hospital for Sick Children, Toronto, Ontario, Canada

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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.

Other names: BSO

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.

Other names: L-PAM

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.

Other names: PBSCT, Autologous Bone marrow Transplant, ABMT

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.

Other names: G-CSF

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.

    Time frame: Within 4 weeks of completion of BSO/L-PAM therapy

Secondary outcomes

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

    Time frame: 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.

    Collection of blood samples for PK studies is optional and not required for study entry.

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

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

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

    Time frame: 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.

    Collection of blood samples for biologic studies is optional and not required for study entry.

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

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

Sponsors and collaborators

Lead sponsor

New Approaches to Neuroblastoma Therapy Consortium

Other

Collaborators

  • National Cancer Institute (NCI)

Registry information

Official study 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)

Acronym: BSO

Important dates

Study start
2001
Primary completion
2014
Study completion
2016
First posted
Jan 27, 2003
Registry last updated
Apr 10, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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