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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)

Phase 1
1 Year
30 Years
Not Enrolling
Disseminated Neuroblastoma, Recurrent Neuroblastoma

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Trial Information

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)


I. 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.


I. 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

Inclusion Criteria:

- 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

- 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)

- 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

Exclusion Criteria:

- 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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose determined by dose-limiting toxicities by NCI Common Toxicity Criteria

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Anna Butturini

Investigator Role:

Principal Investigator

Investigator Affiliation:

New Approaches to Neuroblastoma Treatment (NANT)


United States: Food and Drug Administration

Study ID:




Start Date:

December 2002

Completion Date:

Related Keywords:

  • Disseminated Neuroblastoma
  • Recurrent Neuroblastoma
  • Neuroblastoma



New Approaches to Neuroblastoma Treatment (NANT) Los Angeles, California  90027-6016