N99-02: Melphalan and Buthionine Sulfoximine (BSO)

April 6, 2023 updated by: New Approaches to Neuroblastoma Therapy Consortium

Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) Autologous Stem Cell Support for Resistant or Recurrent High-Risk Neuroblastoma (IND 69-112)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • Hospital for Sick Children
  • United States
    • California
      • Los Angeles, California, United States, 90027-0700
        • Childrens Hospital Los Angeles
      • San Francisco, California, United States, 94143
        • UCSF Helen Diller Family Comprehensive Cancer Center
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago Comer Children's Hospital
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Childrens Hospital Boston, Dana-Farber Cancer Institute.
    • Ohio
      • Cincinnati, Ohio, United States, 45229-3039
        • Cincinnati Children's Hospital Medical Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4318
        • Children's Hospital of Philadelphia
    • Texas
      • Fort Worth, Texas, United States, 76104
        • Cook Children's Medical Center - Fort Worth
    • Washington
      • Seattle, Washington, United States, 98105
        • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single Group
Drug: 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.
Other Names:
  • BSO
Drug: 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.
Other Names:
  • L-PAM
Procedure: 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.
Other Names:
  • PBSCT
  • ABMT
  • Autologous Bone marrow Transplant
Other: 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 Names:
  • G-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
Within 4 weeks of completion of BSO/L-PAM therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
Time Frame: 84 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.
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.
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.
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.
Time Frame: Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.
Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

New Approaches to Neuroblastoma Therapy Consortium

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Samuel Volchenboum, MD, Comer Children's Hospital, University of Chicago

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2001

Primary Completion (Actual)

December 1, 2014

Study Completion (Actual)

April 1, 2016

Study Registration Dates

First Submitted

June 2, 2000

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

April 10, 2023

Last Update Submitted That Met QC Criteria

April 6, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000067849
  • P01CA081403 (U.S. NIH Grant/Contract)
  • NANT-99-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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