RATIONALE: 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.

PURPOSE: 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.

Condition	Treatment or Intervention	Phase
recurrent neuroblastoma disseminated neuroblastoma	Drug: filgrastim  Drug: pyrazoloacridine  Procedure: autologous bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: high-dose chemotherapy  Procedure: peripheral blood stem cell transplantation	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the maximum tolerated dose, in relation to infusion time, of high-dose pyrazoloacridine followed by autologous hematopoietic stem cell rescue in pediatric patients with high-risk neuroblastoma.
• Determine the dose-limiting toxicity of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine, preliminarily, the antitumor activity of this drug in these patients.

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.

• Stage I: Cohorts of 3-6 patients receive escalating doses of PZA at a fixed infusion time until the maximum tolerated dose (MTD) is determined.
• Cohorts of 3-6 patients receive PZA at the MTD/hour at escalating infusion times until another MTD is determined. In both stages 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.

PROJECTED ACCRUAL: A total of 18-42 patients will be accrued for this study.

Ages Eligible for Study:  1 Year   -   30 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed neuroblastoma
• High-risk disease, as defined by the following:
• Mixed response OR no response after completion of ≥ 4 courses of induction therapy OR
• Progressive disease
• Must meet at least 1 of the following criteria:
• Histologically confirmed bone marrow disease by bilateral bone marrow aspirate and biopsy
• Positive uptake at a minimum of one site by iodine I 123 metaiodobenzylguanidine (MIBG) scan
• Measurable disease
• At least 20 mm by CT scan or MRI OR at least 10 mm by spiral CT scan
• No CNS parenchymal metastases by CT scan of the head with contrast or MRI of the head with gadolinium OR epidural metastases causing mass effect on the brain
• Skull metastases allowed provided they are not associated with intracranial disease compressing or displacing the brain

PATIENT CHARACTERISTICS: Age

• 1 to 30

Performance status

• Karnofsky 50-100% (over 16 years of age)
• Lansky 50-100% (1 to 15 years of age)

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count at least 750/mm^3
• Platelet count at least 75,000/mm^3 (transfusion independent)
• Hemoglobin at least 8 g/dL (transfusion allowed)

Hepatic

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 3 times ULN

Renal

• Glomerular filtration rate (GFR)* or creatinine clearance at least 100 mL/min
• Creatinine no greater than 1.5 times ULN NOTE: *Determined using blood draw method only

Cardiovascular

• Ejection fraction at least 55% by echocardiogram or MUGA OR
• Fractional shortening at least 27% by echocardiogram

Pulmonary

• No dyspnea at rest
• No oxygen requirement

Neurologic

• No history of seizures
• No history of cerebral bleeding or stroke
• No acute or chronic CNS disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection requiring IV antivirals, antibiotics, or antifungals
• Patients on prolonged antifungal therapy allowed provided they are culture-negative and biopsy-negative in suspected residual radiographic lesions

PRIOR CONCURRENT THERAPY: Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior myeloid growth factors
• At least 3 weeks since prior biologic agents
• At least 9 months since prior autologous hematopoietic stem cell transplantation (HSCT)
• No prior allogeneic HSCT

Chemotherapy

• See Disease Characteristics
• No prior pyrazoloacridine
• At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas) and recovered

Endocrine therapy

• Not specified

Radiotherapy

• Recovered from prior radiotherapy
• At least 2 weeks since prior small-port radiotherapy to lesions not used for study eligibility
• At least 4 weeks since prior radiotherapy to study lesions
• At least 12 weeks since prior therapeutic doses of metaiodobenzylguanidine
• At least 6 months since prior craniospinal radiotherapy
• At least 6 months since prior radiotherapy to 50% or more of the pelvis
• At least 6 months since prior total body irradiation

Surgery

• Not specified

Other

• No concurrent antiretroviral therapy for HIV-positive patients

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States; Recruiting
      Lucile Packard Children's Hospital at Stanford University Medical Center, Palo Alto,  California,  94304,  United States; Recruiting
      UCSF Comprehensive Cancer Center, San Francisco,  California,  94143,  United States; Recruiting
Georgia
      AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus, Atlanta,  Georgia,  30322,  United States; Recruiting
Illinois
      Children's Memorial Hospital - Chicago, Chicago,  Illinois,  60614,  United States; Recruiting
Indiana
      Riley Children Cancer Center at Riley Hospital for Children, Indianapolis,  Indiana,  46202-5225,  United States; Recruiting
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States; Recruiting
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-6164,  United States; Recruiting

Study chairs or principal investigators

Anna Butturini, MD,  Study Chair,  Children's Hospital Los Angeles   

Study ID Numbers:  CDR0000269644; NANT-N2002-01; CHLA-NANT-N2002-01; NCT00053950
Record last reviewed:  February 2005
Last Updated:  February 15, 2005
Record first received:  February 5, 2003
ClinicalTrials.gov Identifier:  NCT00053950
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08