Decitabine, Doxorubicin, and Cyclophosphamide in Treating Children With Relapsed or Refractory Solid Tumors or Neuroblastoma

Phase 1

Completed

Conditions: Recurrent Neuroblastoma
Unspecified Childhood Solid Tumor, Protocol Specific

Interventions: Drug: decitabine
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Biological: filgrastim
Biological: pegfilgrastim
Other: laboratory biomarker analysis
Other: pharmacological study

Registration Number: NCT00075634

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase I trial is studying the side effects and best dose of decitabine when given together with doxorubicin and cyclophosphamide in treating children with relapsed or refractory solid tumors or neuroblastoma. Drugs used in chemotherapy, such as decitabine, doxorubicin, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of decitabine in combination with doxorubicin and cyclophosphamide in children with relapsed or refractory solid tumors or neuroblastoma.

II. Determine the toxic effects of this regimen in these patients. III. Determine whether decitabine induces tumor caspase-8 demethylation and expression in these patients.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of low-dose decitabine in these patients. II. Determine the biological and clinical response in patients treated with this regimen.

III. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

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
Performance status - Karnofsky 50-100% (patients 11 to 21 years of age)
Performance status - Lansky 50-100% (patients ≤ 10 years of age)
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
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
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)
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
Shortening fraction ≥ 28% by echocardiogram
Ejection fraction of ≥ 45% by MUGA
No significant pulmonary dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results
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
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
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
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
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

Exclusion Criteria

Not provided

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	pegfilgrastim	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	laboratory biomarker analysis	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	filgrastim	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	pharmacological study	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	doxorubicin hydrochloride	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.
Arm I	cyclophosphamide	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. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.

Primary Outcome Measures

Name	Time	Method
MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)	Up to 28 days
Caspase-8 expression in bone marrow or tumor biopsy samples (Part B)	Up to 28 days

Secondary Outcome Measures

Name	Time	Method
Objective response rate	Up to 56 days	Confidence intervals will be reported in addition to the estimated response rates.
Percent of apoptotic cells as assessed by a TUNEL assay	Up to 1 year	A sign test or other appropriate nonparametric test may be used to assess whether there was an increase in the percent of apoptotic cells after treatment.

Trial Locations

Locations (1): Children's Oncology Group
🇺🇸
Arcadia, California, United States

Decitabine, Doxorubicin, and Cyclophosphamide in Treating Children With Relapsed or Refractory Solid Tumors or Neuroblastoma

Recruitment & Eligibility

Study & Design

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