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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- 另有 12 项未显示
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: decitabine (Drug)
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.
干预措施: doxorubicin hydrochloride (Drug)
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.
干预措施: cyclophosphamide (Drug)
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.
干预措施: filgrastim (Biological)
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.
干预措施: pegfilgrastim (Biological)
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.
干预措施: laboratory biomarker analysis (Other)
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.
干预措施: pharmacological study (Other)
结局指标
主要结局
MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)
时间窗: Up to 28 days
Caspase-8 expression in bone marrow or tumor biopsy samples (Part B)
时间窗: Up to 28 days
次要结局
- Percent of apoptotic cells as assessed by a TUNEL assay(Up to 1 year)
- Objective response rate(Up to 56 days)