NeuroblastomaPhase 1BSONCT00005835
N99-02: Melphalan and Buthionine Sulfoximine
A Phase 1 study testing buthionine sulfoximine, melphalan and Peripheral blood stem cell infusion in people with Neuroblastoma, run by New Approaches to Neuroblastoma Therapy Consortium at 9 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 30 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- buthionine sulfoximine, melphalan and Peripheral blood stem cell infusion
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 9 sitesin 2 countries
- Study dates
- Aug 2001to Apr 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
Trial locations and contacts
9 sites in 2 countries.
9 sites in 2 countries
United States8 sites
Childrens Hospital Boston, Dana-Farber Cancer Institute.
Boston, Massachusetts, 02115
University of Chicago Comer Children's Hospital
Chicago, Illinois, 60637
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229-3039
Cook Children's Medical Center - Fort Worth
Fort Worth, Texas, 76104
Childrens Hospital Los Angeles
Los Angeles, California, 90027-0700
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104-4318
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, 94143
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, 98105
About this study
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)
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.
Read the 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.
- Conditions
- Neuroblastoma
- Being tested
- buthionine sulfoximine, melphalan, Peripheral blood stem cell infusion, Filgrastim
- Keywords
- regional neuroblastoma, disseminated neuroblastoma, recurrent neuroblastoma, localized unresectable neuroblastoma
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
buthionine sulfoximineDrug
Also called BSO
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.
melphalanDrug
Also called L-PAM
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 infusionProcedure or surgery
Also called PBSCT, Autologous Bone marrow Transplant, ABMT
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.
FilgrastimOther
Also called G-CSF
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.
| Study group | Role | What they receive |
|---|---|---|
| Single Group | Experimental | Not described Receives: Drug: buthionine sulfoximine; Drug: melphalan; Procedure: Peripheral blood stem cell infusion; Other: Filgrastim |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Collection of blood samples for PK studies is optional and not required for study entry.
Measured: 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.
Measured: 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.
Collection of blood samples for biologic studies is optional and not required for study entry.
Measured: 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.
Measured: Maximum 56 days after completion of therapy with BSO/L-PAM and Stem cell re-infusion.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2003 (estimated)
- Study startAug 2001
- Primary completionDec 2014
- Study completionApr 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- New Approaches to Neuroblastoma Therapy Consortium
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Samuel Volchenboum, MD, Study chair, Comer Children's Hospital, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00005835
- Sponsor's protocol ID
- CDR0000067849
- Other IDs
- P01CA081403, NANT-99-02
- Acronym
- BSO
- Status last verified
- Apr 2023
- First submitted
- 2 Jun 2000
- Last updated
- 10 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 27092812
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT00005835
- Acronym / sponsor ID
- BSO / CDR0000067849
- Conditions
- Neuroblastoma
- Keywords
- regional neuroblastoma, disseminated neuroblastoma, recurrent neuroblastoma, localized unresectable neuroblastoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- New Approaches to Neuroblastoma Therapy ConsortiumUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Aug 2001
- Primary completion
- Dec 2014 (actual)
- Study completion
- Apr 2016 (actual)
- First posted
- 27 Jan 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Group | Experimental | Drug: buthionine sulfoximine, Drug: melphalan, Procedure: Peripheral blood stem cell infusion, Other: Filgrastim |
Who may qualify
- Ages
- Up to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (9 listed)
- 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)).
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| buthionine sulfoximineAlso: BSODose 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. | Drug | Single Group |
| melphalanAlso: L-PAMThe 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. | Drug | Single Group |
| Peripheral blood stem cell infusionAlso: PBSCT, Autologous Bone marrow Transplant, ABMTStem 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. | Procedure or surgery | Single Group |
| FilgrastimAlso: G-CSF5 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 | Single Group |
Primary outcome
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
4 secondary outcomes
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.
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.
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Apr 2023.
- Background: PubMed 27092812Villablanca 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Samuel Volchenboum, MD study chair
Comer Children's Hospital, University of Chicago
9 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing buthionine sulfoximine, melphalan and Peripheral blood stem cell infusion in people with Neuroblastoma, run by New Approaches to Neuroblastoma Therapy Consortium at 9 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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. (time frame: Within 4 weeks of completion of BSO/L-PAM therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00005835, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2023.