A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in Combination With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 32
- 主要终点
- Number of Patients That Experienced DLT During Cycle 1 of Therapy
研究概览
简要总结
This is a phase I study of temsirolimus (Torisel) combined with dexamethasone, cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).
详细描述
Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect due to conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease (MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Temsirolimus (Drug)
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Etoposide (Drug)
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cyclophosphamide (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Etoposide (Drug)
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Methotrexate (Drug)
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Hydrocortisone (Drug)
Dose Level 1
This is the starting dose of temsirolimus at 7.5 mg/m^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cytarabine (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Temsirolimus (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cyclophosphamide (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Methotrexate (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Hydrocortisone (Drug)
Dose Level 2
If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cytarabine (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Temsirolimus (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Etoposide (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cyclophosphamide (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Methotrexate (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Hydrocortisone (Drug)
Dose Level 3
If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.
干预措施: Cytarabine (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Temsirolimus (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Etoposide (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Cyclophosphamide (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Methotrexate (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Hydrocortisone (Drug)
Dose Level 4
If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m^2) and cyclophosphamide (440 mg/m^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
干预措施: Cytarabine (Drug)
结局指标
主要结局
Number of Patients That Experienced DLT During Cycle 1 of Therapy
时间窗: Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy. All these analyses will be descriptive and exploratory and hypotheses generating in nature.
次要结局
- Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients(Cycle 1 (a minimum of 4 weeks and a max of 8 weeks))
- Response Rate at the Completion of 1 Cycle of Study Treatment(Cycle 1 (a minimum of 4 weeks and a max of 8 weeks))