• Toxicity [ Designated as safety issue: Yes ]
  

• Caspase-8 expression [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of decitabine in combination with doxorubicin and cyclophosphamide in children with relapsed or refractory solid tumors or neuroblastoma.
• Determine the toxic effects of this regimen in these patients.
• Determine whether decitabine induces tumor caspase-8 demethylation and expression in these patients.

Secondary

• Determine the pharmacokinetics of low-dose decitabine in these patients.
• Determine the biological and clinical response in patients treated with this regimen.
• Compare patterns of peripheral blood gene expression, using gene expression profiling, in patients before and after treatment with decitabine.

OUTLINE: This is a multicenter, dose-escalation study of decitabine.

• Part A (solid tumor patients): Patients receive decitabine IV over 1 hour on days 0-6 and doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on day 7. Patients then receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 8 and continuing until blood counts recover OR pegfilgrastim SC once on day 8 or 9*. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine 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.

NOTE: *For patients > 45 kg

• Part B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD .

Patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 15-21 patients will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of either of the following:

  • Solid tumor (part A)

    • No lymphoma

  • Neuroblastoma (part B)

    • Original diagnosis may be based on elevated urine vanillylmandelic acid (VMA) and homovanillic acid (HVA) and bone marrow examination

    • Accessible disease by bone marrow aspirate or tumor biopsy

      • No laparotomy, thoracotomy, endoscopy, or craniotomy for biopsy
• No known curative therapy OR therapy proven to prolong survival with an acceptable quality of life available
• No known brain or spinal cord metastases
• No CNS tumors

PATIENT CHARACTERISTICS:

Age

• Over 12 months to 21 years

Performance status

• Karnofsky 50-100% (patients 11 to 21 years of age)
• Lansky 50-100% (patients ≤ 10 years of age)

Life expectancy

• Not specified

Hematopoietic

• Parts A and B without bone marrow infiltration:

  • Absolute neutrophil count ≥ 1,000/mm^3
  • Platelet count ≥ 100,000/mm^3 (transfusion independent)

• Part B with bone marrow infiltration (i.e., tumor metastatic to bone marrow with granulocytopenia, anemia, and/or thrombocytopenia):

  • Absolute neutrophil count ≥ 750/mm^3
  • Platelet count ≥ 50,000/mm^3 (transfusion independent)
• Hemoglobin ≥ 8.0 g/dL (transfusion allowed)
• No sickle cell anemia

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• ALT ≤ 5 times upper limit of normal
• No significant hepatic dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results

Renal

• Creatinine based on age as follows:

  • ≤ 0.8 mg/dL (5 years of age and under)
  • ≤ 1.0 mg/dL (6 to 10 years of age)
  • ≤ 1.2 mg/dL (11 to 15 years of age)
  • ≤ 1.5 mg/dL (16 to 21 years of age) OR
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
• No significant renal dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results

Cardiovascular

• Shortening fraction ≥ 28% by echocardiogram OR
• Ejection fraction of ≥ 45% by MUGA

Pulmonary

• No significant pulmonary dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to agents used in this study
• No uncontrolled serious infection
• No significant end-organ dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior biologic therapy
• More than 1 week since prior growth factor therapy (2 weeks for pegfilgrastim)
• More than 2 weeks since prior epoetin alfa
• At least 6 months since prior autologous stem cell transplantation

• At least 6 months since prior allogeneic bone marrow transplantation

  • Patients must have full organ recovery and no evidence of graft-versus-host disease
• No concurrent immunomodulating agents
• No concurrent immunotherapy
• No concurrent biologic therapy
• No concurrent epoetin alfa

Chemotherapy

• Recovered from prior chemotherapy
• More than 2 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
• Prior total lifetime cumulative anthracycline dose ≤ 450 mg/m^2 of doxorubicin or equivalent
• No other concurrent chemotherapy
• No concurrent hydroxyurea

Endocrine therapy

• Not specified

Radiotherapy

• Recovered from prior radiotherapy
• More than 2 weeks since prior local palliative small port radiotherapy
• More than 6 months since prior substantial bone marrow irradiation (e.g., cranio-spinal irradiation, total body irradiation, or hemi-pelvic irradiation)
• No concurrent radiotherapy

Surgery

• Not specified

Other

• No other concurrent anticancer therapy
• No other concurrent investigational agents
• Concurrent oral iron supplementation for patients with a known iron deficiency or a microcytic hypochromic anemia allowed