A Phase I Study of Decitabine (NSC# 127716, IND# 50733) in Combination With Doxorubicin and Cyclophosphamide in the Treatment of Relapsed or Refractory Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- decitabine
- Conditions
- Recurrent Neuroblastoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)
- Status
- Completed
- Last Updated
- 12 years ago
Overview
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.
Investigators
Eligibility Criteria
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
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
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.
Intervention: decitabine
Arm I
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.
Intervention: doxorubicin hydrochloride
Arm I
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.
Intervention: cyclophosphamide
Arm I
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.
Intervention: filgrastim
Arm I
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.
Intervention: pegfilgrastim
Arm I
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.
Intervention: laboratory biomarker analysis
Arm I
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.
Intervention: pharmacological study
Outcomes
Primary Outcomes
MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)
Time Frame: Up to 28 days
Caspase-8 expression in bone marrow or tumor biopsy samples (Part B)
Time Frame: Up to 28 days
Secondary Outcomes
- Percent of apoptotic cells as assessed by a TUNEL assay(Up to 1 year)
- Objective response rate(Up to 56 days)