Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 17
- 主要终点
- Phase 1: Maximum Tolerated Dose (MTD) of Cytarabine
研究概览
简要总结
The purpose of this study is to examine the safety and efficacy of decitabine in sequential administration with cytarabine in children with relapsed or refractory acute myeloid leukemia (AML).
详细描述
This is an open-label (identity of assigned study drug will be known) study to evaluate safety, efficacy, and pharmacokinetics (study of what the body does to a drug) of decitabine in sequential administration with cytarabine in children with relapsed or refractory AML. The study will determine the maximum tolerated dose of cytarabine that can be given following decitabine (Phase 1) and the response rate to this combination (Phase 2). Participants may enter a continuation phase of single agent-decitabine infusions for as long as such treatment would be considered beneficial. Serial pharmacokinetic samples will be collected and safety and efficacy will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological diagnosis of acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification
- •Diagnosis of AML which has relapsed or is refractory to standard of care and no curative therapy exists
- •Karnofsky or Lansky score of at least 50
- •Must be recovered from acute toxicity of any prior treatment
- •Must have adequate organ function according to protocol-defined criteria
- •Agrees to protocol-defined use of effective contraception
- •Female participants of childbearing potential must have a negative serum or urine pregnancy test at Day 1 of Cycle 1
排除标准
- •Prior treatment with decitabine or azacitidine
- •Acute promyelocytic leukemia (M3 subtype in the French-American-British [FAB] classification system)
- •CNS3 disease
- •acute myeloid leukemia (AML) associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome or Diamond-Blackfan anemia, or bone marrow failure associated with inherited syndromes
- •White blood cell count greater than 40x10^9 cells/liter(L)
- •Known allergies, hypersensitivity, or intolerance to decitabine or cytarabine or their excipients
- •Contraindications to the use of cytarabine per local prescribing information or prior adverse reactions to cytarabine which would prevent further use
- •Currently enrolled in the treatment phase of an interventional investigational study
- •Female who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug (however, the period after which it becomes safe to become pregnant after the last dose of treatment is not known)
- •Male who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
- •Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments
- •Any social or medical condition that in the investigator's opinion renders the participant unfit for study participation
- •History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease
- •History of human immunodeficiency virus (HIV) antibody positive
研究组 & 干预措施
Decitabine and cytarabine
干预措施: Phase1 and Phase 2: decitabine (Drug)
Decitabine and cytarabine
干预措施: Phase 1: cytarabine (Drug)
Decitabine and cytarabine
干预措施: Phase 2: cytarabine (Drug)
结局指标
主要结局
Phase 1: Maximum Tolerated Dose (MTD) of Cytarabine
时间窗: Cycle 1 (42 days)
The maximum tolerated dose (MTD) for cytarabine was based on the number of participants experiencing a dose-limiting toxicity (DLT) by the end of Cycle 1. A non-hematological DLT was defined as: any Grade \>=3 toxicity that persists for greater than (\>) 5 days or any Grade 2 toxicity that persists for \>7 days and that is intolerable to the participant. A hematological DLT was defined as Grade 4 neutropenia or thrombocytopenia due to a hypoplastic bone marrow at Day 42, in the absence of malignant infiltration. The nominal duration of each cycle was 28 days. However, participants who had not experienced bone marrow recovery at Day 28 were followed up to Day 42. Failure of marrow recovery (improvement to Grade 3) by Day 42 was considered a DLT. The maximum duration of Cycle 1 was therefore 42 days.
Phase 1 and 2: Total Clearance of Decitabine
时间窗: Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 minute (min), 0.5 hour, 1 hour, and 2 hour after end of infusion
Total clearance of drug after intravenously administration was calculated as: dose/area under the plasma concentration-time curve.
Phase 1 and 2: Volume of Distribution at Steady-State (Vss) of Decitabine
时间窗: Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 1 Day 28
时间窗: Cycle 1 (28 days) Day 28
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 2 Day 28
时间窗: Cycle 2 (28 days) Day 28
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Phase 2: Percentage of Participants Who Achieved CR or CRi at End of Study Treatment
时间窗: End of study treatment (approximately 3 years)
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than \[\<\] 1,000/microliter) or thrombocytopenia \<100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (\>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (\>) 1,000/ microliter, platelet count of \>100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
次要结局
- Phase 1 and 2: Maximum Plasma Concentration (Cmax) of Decitabine(Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion)
- Phase 1 and 2: Area Under the Plasma Concentration-Time Curve (AUC) of Decitabine(Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion)
- Phase 2: Duration of Response(From time of response to relapse, study completion/withdrawal, or death, whichever comes first, for up to approximately 3 years 10 months)
- Phase 2: Overall Response Rate(Up to approximately 3 years 10 months)
- Phase 1 and 2: Overall Survival (OS)(From enrollment to death or withdrawal, whichever comes first, for up to approximately 3 years 10 months)
- Phase 1 and 2: Event-Free Survival(From enrollment to progression/relapse, death, or withdrawal, whichever comes first, for up to approximately 3 years 10 months)
- Phase 1 and 2: Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)(Approximately 3 years 10 months)