Disseminated NeuroblastomaPhase 1NCT00053950
Pyrazoloacridine and Stem Cell or Bone Marrow Transplantation in Treating Young Patients With High-Risk Neuroblastoma
A Phase 1 study testing pyrazoloacridine, filgrastim and autologous bone marrow transplantation in people with Disseminated Neuroblastoma and Recurrent Neuroblastoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This phase I trial is studying the side effects and best dose of pyrazoloacridine given together with peripheral stem cell or bone marrow transplantation in treating young patients with high-risk neuroblastoma. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Read more about this study
- Who is it for?
- Ages 1 year to 30 years
- Conditions the study is for
- Disseminated Neuroblastoma, Recurrent Neuroblastoma
- What is being tested?
- pyrazoloacridine, filgrastim and autologous bone marrow transplantation
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2002to Mar 2007
- 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 1 year to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites
- Patients must meet one of the two following disease status criteria to enter on study;
- Current or prior progressive disease (PD) by INRC criteria
- Either mixed response (MR) or no response (NR) by INRC criteria following completion of minimum of 4 courses of induction therapy
- Patients meeting disease status criteria in either category A or B must also have at least one of the following sites of disease present to enter on study:
- At least one tumor lesion on CT or MRI scan that is >= 20mm in at least one dimension (spiral CT lesion must be >= 10mm in at least one dimension)
Show all 27Show fewer
- MIBG scan with positive uptake at a minimum of one site
- Bone marrow disease documented by standard histology of bilateral bone marrow aspirate and biopsy specimens
- Patients > 16 years of age: Karnofsky >= 50%; Patients =< 16 years of age: Lansky >= 50%; patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score; life expectancy must be >= 2 months for all patients
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Chemotherapy and/or biologics: Must not have received treatment within 3 weeks of entry onto this study (4 weeks if prior nitrosureas
- Radiation: At least 4 weeks since last dose of radiation therapy to at least one lesion being used as criteria for study eligibility; only 2 weeks must elapse since the last dose of radiation (small port) to a lesion not used for study eligibility; at least 6 months must have elapsed since the last dose of prior craniospinal XRT and radiation to >= 50% of the pelvis or TBI
- Stem Cell Transplant (SCT): >= 9 months must have elapsed since autologous hematopoietic stem cell transplant (aHSCT)
- Prior MIBG therapy: At least 12 weeks must have elapsed since treatment with therapeutic doses of MIBG
- Study specific limitations on prior therapy: patients who have a history of allogeneic HSCT are not eligible
- Growth factor(s): At least 7 days since the last dose of any myeloid growth factor was given
- Any patient considered for this protocol must meet the following criteria for minimum number of autologous stem cells sufficient to rescue hematopoiesis; a combination of products may be used to meet this requirement
- All stem cell products infused on this protocol must meet the following criteria for tumor analysis: No tumor cells detectable by immunocytology OR for patients who had a PBSC collection done previously and no immunocytological testing was done on the product at the time of collection: This product may be used for infusion on this study if the patient's bilateral bone marrow aspirate and biopsy specimens can be shown to be tumor free by standard histology within 4 weeks of PBSC collection
- Glomerular filtration rate (GFR) using blood draw method or 12 hour urine collection for creatinine clearance >= 100 ml/min/1.73 m^2
- Serum creatinine =< 1.5 x upper limit of normal for age
- Normal ejection fraction (>= 55%) documented by echocardiogram or radionuclide MUGA evaluation OR normal fractional shortening (>= 27%) documented by echocardiogram
- Total bilirubin < 1.5 x upper limit of normal
- AST/ALT =< 3 x upper limit of normal
- Platelets >= 75,000/uL (transfusion independent)
- Hemoglobin >= 8 g/dl (transfusion allowed)
- Because evaluation of hematopoietic toxicity is essential to this study, the same criteria will be applied to patients with tumor infiltration of the bone marrow
- Normal lung function as manifested by no dyspnea at rest and no oxygen requirement
Who cannot join
- No patients who are pregnant or lactating will be allowed to enter on study; pregnancy tests must be obtained in females who are post-menarchal; males and females of reproductive potential may not participate unless they have agreed to use an effective method of contraception while receiving therapy
- Patients with active infections requiring intravenous antivirals, antibiotics, or antifungals; patients on prolonged antifungal therapy are still eligible if they are culture negative and biopsy negative in suspected residual radiographic lesions and they meet other organ function criteria; patients who are known HIV seropositive with stable disease and lack of major health problems who are not on anti-retroviral therapy, may be eligible at the discretion of the Study Chair
- Prior treatment with Pyrazoloacridine (PZA)
- Prior history of allogeneic HSCT
- Neurologic Exclusions:
- Acute or chronic CNS disease
Show all 9Show fewer
- History of seizures
- History of cerebral bleeding or stroke
- CNS parenchymal metastases as documented by head CT with contrast or head MRI with gadolinium performed within 30 days of study entry. Patients with epidural metastases causing mass effect on the brain are also excluded (skull metastases are allowed provided they are not associated with intracranial disease compressing or displacing the brain
Trial locations and contacts
1 site in 1 country.
United States1 site
New Approaches to Neuroblastoma Treatment (NANT)
Los Angeles, California, 90027-6016
About this study
Official title: A Phase I Study of High-dose Pyrazoloacridine (PZA) (NSC 366140) Supported With Autologous Hematopoietic Stem Cell Rescue in Children With Recurrent or Resistant Neuroblastoma (IND # 36325)
This phase I trial is studying the side effects and best dose of pyrazoloacridine given together with peripheral stem cell or bone marrow transplantation in treating young patients with high-risk neuroblastoma. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the maximum tolerated dose (MTD) of PZA given as a single prolonged infusion (>= 6 hours) with autologous hematopoietic stem cell (aHSC) support to children with high risk neuroblastoma with recurrent or refractory disease.
II. To determine the dose limiting toxicity (DLT) of PZA given on this schedule.
III. To characterize the pharmacokinetics of PZA given on this schedule.
SECONDARY OBJECTIVES:
- To obtain preliminary data on the antitumor activity of PZA within the confines of a Phase I study.
II. To determine the TP53 mutation status of tumor cells in bone marrow if > 10% are present; to evaluate expression of p53 and MDM2 proteins by flow cytometry if >= 0.1% to < 10% are present at study entry.
OUTLINE: This is a two-stage, dose-escalation study.
Patients without adequate cryopreserved hematopoietic stem cells undergo peripheral blood stem cell harvest or bone marrow harvest for autologous stem cells at least 2 weeks before study therapy.
Patients receive high-dose pyrazoloacridine (PZA) IV on day 0.
Cohort 1: Groups of 3-6 patients receive escalating doses of PZA at a fixed infusion time until the maximum tolerated dose (MTD) is determined.
Cohort 2: Groups of 3-6 patients receive PZA at the dose/hour established in cohort I at escalating infusion times until another MTD is determined.
In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol.
Patients are followed at days 28-35, every 3 months for 3 years, and then every 6 months thereafter.
- Being tested
- pyrazoloacridine, filgrastim, autologous bone marrow transplantation, peripheral blood stem cell transplantation, laboratory biomarker analysis
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
pyrazoloacridineDrug
Also called PZA
Given IV
filgrastimBiological
Also called G-CSF, Neupogen
Given IV or SC
autologous bone marrow transplantationProcedure or surgery
Also called ABMT, bone marrow transplantation, autologous, transplantation, autologous bone marrow
Undergo autologous bone marrow transplantation
peripheral blood stem cell transplantationProcedure or surgery
Also called PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Undergo peripheral blood stem cell transplantation
laboratory biomarker analysisOther
Correlative studies
Also called pharmacological studies
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Cohort I | Experimental | Groups of 3-6 patients receive escalating doses of PZA at a fixed infusion time until the MTD is determined. In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients receive G-CSF IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol. Receives: Drug: pyrazoloacridine; Biological: filgrastim; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Other: laboratory biomarker analysis; Other: pharmacological study |
| Cohort II | Experimental | Groups of 3-6 patients receive PZA at the dose/hour established in cohort I at escalating infusion times until another MTD is determined. In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients receive G-CSF IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol. Receives: Drug: pyrazoloacridine; Biological: filgrastim; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Other: laboratory biomarker analysis; Other: pharmacological study |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose determined by dose-limiting toxicities by NCI Common Toxicity Criteria
Measured: 28 days
Secondary outcomes (6)
Time to engraftment (hematopoietic recovery)
Will be summarized with tables and with Kaplan-Meier plots.
Measured: Up to 4 years
Response by RECIST or MIBG-scans
Measured: 28 days
Survival
Measured: Up to 4 years
Time to progression
Measured: Up to 4 years
Time to failure
Measured: Time from start of treatment until death for any cause or disease progression, assessed up to 4 years
Pharmacokinetic (such as AUC, Cmax, Tmax, and clearance in the plasma) determinations
Will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations.
Measured: 3, 24, 72,and 192 hours after starting infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2003 (estimated)
- Study startDec 2002
- Primary completionMar 2007
Why it stopped: Administratively complete.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Disseminated NeuroblastomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- 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
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Anna Butturini, Principal investigator, New Approaches to Neuroblastoma Treatment (NANT)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00053950
- Sponsor's protocol ID
- NCI-2012-03166
- Other IDs
- NANT N2002-01, P01CA081403, CHLA-NANT-N2002-01, CDR0000269644
- Status last verified
- Apr 2013
- First submitted
- 5 Feb 2003
- Last updated
- 9 Apr 2013
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of High-dose Pyrazoloacridine (PZA) (NSC 366140) Supported With Autologous Hematopoietic Stem Cell Rescue in Children With Recurrent or Resistant Neuroblastoma (IND # 36325)
- ClinicalTrials.gov ID
- NCT00053950
- Acronym / sponsor ID
- NCI-2012-03166
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Administratively complete.
- Enrolment
- 42 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Dec 2002
- Primary completion
- Mar 2007 (actual)
- First posted
- 6 Feb 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.
This phase I trial is studying the side effects and best dose of pyrazoloacridine given together with peripheral stem cell or bone marrow transplantation in treating young patients with high-risk neuroblastoma. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES:
- To determine the maximum tolerated dose (MTD) of PZA given as a single prolonged infusion (>= 6 hours) with autologous hematopoietic stem cell (aHSC) support to children with high risk neuroblastoma with recurrent or refractory disease.
II. To determine the dose limiting toxicity (DLT) of PZA given on this schedule.
III. To characterize the pharmacokinetics of PZA given on this schedule.
SECONDARY OBJECTIVES:
- To obtain preliminary data on the antitumor activity of PZA within the confines of a Phase I study.
II. To determine the TP53 mutation status of tumor cells in bone marrow if > 10% are present; to evaluate expression of p53 and MDM2 proteins by flow cytometry if >= 0.1% to < 10% are present at study entry.
OUTLINE: This is a two-stage, dose-escalation study.
Patients without adequate cryopreserved hematopoietic stem cells undergo peripheral blood stem cell harvest or bone marrow harvest for autologous stem cells at least 2 weeks before study therapy.
Patients receive high-dose pyrazoloacridine (PZA) IV on day 0.
Cohort 1: Groups of 3-6 patients receive escalating doses of PZA at a fixed infusion time until the maximum tolerated dose (MTD) is determined.
Cohort 2: Groups of 3-6 patients receive PZA at the dose/hour established in cohort I at escalating infusion times until another MTD is determined.
In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol.
Patients are followed at days 28-35, every 3 months for 3 years, and then every 6 months thereafter.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort I | Experimental | Drug: pyrazoloacridine, Biological: filgrastim, Procedure: autologous bone marrow transplantation, Procedure: peripheral blood stem cell transplantation, Other: laboratory biomarker analysis, Other: pharmacological studyGroups of 3-6 patients receive escalating doses of PZA at a fixed infusion time until the MTD is determined. In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients receive G-CSF IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol. |
| Cohort II | Experimental | Drug: pyrazoloacridine, Biological: filgrastim, Procedure: autologous bone marrow transplantation, Procedure: peripheral blood stem cell transplantation, Other: laboratory biomarker analysis, Other: pharmacological studyGroups of 3-6 patients receive PZA at the dose/hour established in cohort I at escalating infusion times until another MTD is determined. In both cohorts the MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients receive G-CSF IV or subcutaneously beginning on day 4 and continuing until blood counts recover. Patients also undergo reinfusion of stem cells over 15-30 minutes on day 4 as needed per protocol. |
Who may qualify
- Ages
- 1 year to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (27 listed)
- Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites
- Patients must meet one of the two following disease status criteria to enter on study;
- Patients meeting disease status criteria in either category A or B must also have at least one of the following sites of disease present to enter on study:
- Patients > 16 years of age: Karnofsky >= 50%; Patients =< 16 years of age: Lansky >= 50%; patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score; life expectancy must be >= 2 months for all patients
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
Key exclusion criteria (9 listed)
- No patients who are pregnant or lactating will be allowed to enter on study; pregnancy tests must be obtained in females who are post-menarchal; males and females of reproductive potential may not participate unless they have agreed to use an effective method of contraception while receiving therapy
- Patients with active infections requiring intravenous antivirals, antibiotics, or antifungals; patients on prolonged antifungal therapy are still eligible if they are culture negative and biopsy negative in suspected residual radiographic lesions and they meet other organ function criteria; patients who are known HIV seropositive with stable disease and lack of major health problems who are not on anti-retroviral therapy, may be eligible at the discretion of the Study Chair
- Prior treatment with Pyrazoloacridine (PZA)
- Prior history of allogeneic HSCT
- Neurologic Exclusions:
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 |
|---|---|---|
| pyrazoloacridineAlso: PZAGiven IV | Drug | Cohort I, Cohort II |
| filgrastimAlso: G-CSF, NeupogenGiven IV or SC | Biological | Cohort I, Cohort II |
| autologous bone marrow transplantationAlso: ABMT, bone marrow transplantation, autologous, transplantation, autologous bone marrowUndergo autologous bone marrow transplantation | Procedure or surgery | Cohort I, Cohort II |
| peripheral blood stem cell transplantationAlso: PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cellUndergo peripheral blood stem cell transplantation | Procedure or surgery | Cohort I, Cohort II |
| laboratory biomarker analysisCorrelative studies | Other | Cohort I, Cohort II |
| pharmacological studyAlso: pharmacological studiesCorrelative studies | Other | Cohort I, Cohort II |
Primary outcome
Maximum tolerated dose determined by dose-limiting toxicities by NCI Common Toxicity Criteria
Time frame: 28 days
6 secondary outcomes
Time to engraftment (hematopoietic recovery)
Time frame: Up to 4 years
Response by RECIST or MIBG-scans
Time frame: 28 days
Survival
Time frame: Up to 4 years
Time to progression
Time frame: Up to 4 years
Time to failure
Time frame: Time from start of treatment until death for any cause or disease progression, assessed up to 4 years
Pharmacokinetic (such as AUC, Cmax, Tmax, and clearance in the plasma) determinations
Time frame: 3, 24, 72,and 192 hours after starting infusion
Results and safety
The study was stopped early (reason given: Administratively complete.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Apr 2013.
Related trials for Disseminated Neuroblastoma
RecruitingPhase 2
A Study of a Vaccine in Combination With Beta-glucan in People With Neuroblastoma
Neuroblastoma, High-risk Neuroblastoma
Active, not recruitingObservational study
Late Effects After Treatment in Patients With Previously Diagnosed High-Risk Neuroblastoma
Recurrent Neuroblastoma, Stage 2A Neuroblastoma
Not yet recruitingEarly Phase 1
GSL Synthetase Inhibitor Plus GM-CSF and/ or Immune Checkpoint Inhibitor in Previously Treated High-Risk Neuroblastoma.
Neuroblastoma
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.
Anna Butturini principal investigator
New Approaches to Neuroblastoma Treatment (NANT)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing pyrazoloacridine, filgrastim and autologous bone marrow transplantation in people with Disseminated Neuroblastoma and Recurrent Neuroblastoma, run by National Cancer Institute (NCI) at 1 site in United States.
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 27 inclusion and 9 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: stopped early, as of the sponsor's last update on 9 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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 was stopped early (reason given: Administratively complete.). Results are not available in the source record.
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?
Maximum tolerated dose determined by dose-limiting toxicities by NCI Common Toxicity Criteria (time frame: 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 9 Apr 2013.