A Phase 1/2 Dose-Escalation Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Pediatric Patients With Refractory or Relapsed Acute Leukemias.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 13
- 主要终点
- Maximum Tolerated Dose (MTD) in Phase 1
研究概览
简要总结
Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
The purpose of the phase 1 portion of this study was to determine if clofarabine added to a combination of etoposide and cyclophosphamide is safe in children with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). The purpose of the phase 2 portion of the study was to measure the effectiveness of the combination therapy in children with ALL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •NOTE: the following eligibility criteria were applicable to acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
- •ALL with > 25% blasts in bone marrow; AML with ≥ 5% blasts in bone marrow; ALL and AML patients may have extramedullary disease
- •Karnofsky Performance Status ≥ 50 for patients > 10 years old; Lansky Performance Status ≥ 50 for patients ≤ 10 years old
- •Prior therapy: AML: 1-2 prior induction regimens and ≤ 1 hematopoietic stem cell transplant (HSCT); ALL: 1-3 prior induction regimens
- •Adequate liver, renal, pancreatic, and cardiac function
- •Have received no prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)
排除标准
- •NOTE: the following eligibility criteria were applicable to ALL and AML patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
- •Burkitt's leukemia
- •Previous treatment with clofarabine
- •Uncontrolled systemic fungal, bacterial or other infection and 48 hrs negative blood cultures required for patients with a history of fever within 3 days of enrollment
- •Active CNS involvement (i.e., should be CNS1 or CNS2)
- •Inadequate time since last therapy: ≤ 14 days since last cytotoxic chemotherapy; ≤ 7 days since last biologic therapy; ≤ 14 days since last monoclonal antibody therapy
- •Have received prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)
- •Pregnant or lactating
- •Have tested positive for hepatitis B or hepatitis C infection or history of cirrhosis
研究组 & 干预措施
clofarabine, etoposide, cyclophosphamide
Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
干预措施: clofarabine (Drug)
clofarabine, etoposide, cyclophosphamide
Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
干预措施: Etoposide (Drug)
clofarabine, etoposide, cyclophosphamide
Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) in Phase 1
时间窗: Up to Day 42 (Phase 1 portion of study)
The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused \<= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD.
Participants With Dose Limiting Toxicity in Phase 1
时间窗: Up to Day 42 (Phase 1 portion of study)
The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.
Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2
时间窗: Approximately 28-56 days (Phase 2 portion of study)
Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): plt ≥20 to \<75 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
次要结局
- Summary of Participants With Adverse Events (AEs) in Phase 1(Up to 9.5 months (Phase 1 portion of study))
- Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1(Approximately 2 months (Phase 1 portion of study))
- Time to Remission for Participants Who Had a Response in Phase 1(up to 8 weeks (Phase 1 portion of study))
- Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1(Up to 2 years (Phase 1 portion of study))
- Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1(Up to 2 years (Phase 1 portion of study))
- Number of Participants With 4-month Event Free Survival in Phase 1(4 months (Phase I portion of study))
- Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1(Up to 2 years (Phase 1 portion of study))
- Summary of Participants With Adverse Events (AEs) in Phase 2(Up to 9.5 months (Phase 2 portion of study))
- Time to Remission for Participants Who Had a Response in Phase 2(up to 8 weeks (Phase 2 portion of study))
- Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2(Up to 2 years (Phase 2 portion of study))
- Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2(Up to 2 years (Phase 2 portion of study))
- Number of Participants With 4-month Event Free Survival in Phase 2(4 months (Phase 2 portion of study))
- Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2(Up to 2 years (Phase 2 portion of study))