A Phase I Study of Talazoparib (BMN 673) Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) of temozolomide combined with talazoparib
研究概览
简要总结
The drug, talazoparib, seems to work against cancer in test tubes and animals by preventing DNA repair in damaged cells leading to their death. Investigators do not know if talazoparib combined with irinotecan will work in humans. Talazoparib has been used in only a small number of adults and children, and there is much not yet known about it.
In Arm A of this study, investigators seek to find the safest dose of irinotecan to give with talazoparib to children and young adults. In a phase I study, different dose levels of drug may be tested. The first 2 or 3 patients will be given a dose, and if none of them has a bad side-effect, the next 2 or 3 patients will be given a higher dose. No temozolomide will be given in in Arm A.
The experimental drug combination of talazoparib and irinotecan will be tested in the hopes of finding a treatment that may be effective against recurrent or refractory solid tumors. The goals of study Arm A are:
- To determine whether the combination of talazoparib and irinotecan is a beneficial treatment for your cancer;
- To learn what kind of side effects talazoparib can cause;
- To learn what kind of side effects talazoparib in combination with irinotecan can cause;
- To learn more about the biology of talazoparib in children diagnosed with solid tumors.
The purpose of Arm B is to to find the safest doses of irinotecan and temozolomide to give with talazoparib to children and young adults with a solid malignancy.. Talazoparib belongs to a family of drugs called "poly ADP ribose polymerase or PARP inhibitors." Irinotecan and temozolomide belong to a family of drugs called "DNA damaging agents."
There are two arms of this trial, A and B. In this study, investigators hope that irinotecan (administered in Arm A) and irinotecan plus temozolomide (administered in Arm B) will damage the DNA of the cancer cells. Then, talazoparib (which is a PARP inhibitor) will block the repair of the cancer cell's damaged DNA, causing the cancer cell to die (a process called "apoptosis").
There are different types of cancers found in children and young adults which appear to be vulnerable to the combination of chemotherapy agents that will be given in this study. Work carried out in the lab show that these agents may be very promising in the treatment of ewing sarcoma, germ cell tumors, wilms tumor, medulloblastoma and possibly neuroblastoma.
详细描述
In Arm A of this study, talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled participant. Both oral talazoparib and intravenous (IV) irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days.
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study (Arm B) will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, on days 1-6. Intravenous irinotecan and oral temozolomide will be given on days 2-6. The study will estimate the maximum tolerated doses, describe the toxicities of therapy, estimate the response rate and characterize the pharmacokinetics of the combined talazoparib plus irinotecan with or without temozolomide.
This study is a traditional dose escalation study using a standard 3+3 phase I design. In Arm A, six or more dose levels will be evaluated for the combination of talazoparib and irinotecan. Once the MTDs of Arm A are determined, Arm B will open and evaluate the combination of talazoparib, irinotecan and temozolomide.
PRIMARY OBJECTIVES - ARM A
- To estimate the maximum tolerated doses (MTDs) of talazoparib (daily, days 1-6) combined with irinotecan (daily, days 2-6) given every 21 days in children with refractory or recurrent solid malignancies.
- To identify and describe the dose limiting toxicities of talazoparib and irinotecan administered in combination to patients with refractory or recurrent solid malignancies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 25 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
Arm A: Talazoparib Plus Irinotecan
Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
Arm A is closed to enrollment.
干预措施: Talazoparib (Drug)
Arm A: Talazoparib Plus Irinotecan
Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
Arm A is closed to enrollment.
干预措施: Irinotecan (Drug)
Arm A: Talazoparib Plus Irinotecan
Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
Arm A is closed to enrollment.
干预措施: Filgrastim (Drug)
Arm A: Talazoparib Plus Irinotecan
Talazoparib will be administered orally on day 1 either once or twice per day depending on the dose level of the enrolled patient. Both oral talazoparib and IV irinotecan will then be administered daily, on days 2-6. Each cycle will last 21 days. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
Arm A is closed to enrollment.
干预措施: Peg-filgrastim (Drug)
Arm B: Talazoparib Plus Irinotecan Plus Temozolomide
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
干预措施: Talazoparib (Drug)
Arm B: Talazoparib Plus Irinotecan Plus Temozolomide
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
干预措施: Irinotecan (Drug)
Arm B: Talazoparib Plus Irinotecan Plus Temozolomide
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
干预措施: Temozolomide (Drug)
Arm B: Talazoparib Plus Irinotecan Plus Temozolomide
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
干预措施: Filgrastim (Drug)
Arm B: Talazoparib Plus Irinotecan Plus Temozolomide
Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a second arm of the study will open administering talazoparib, irinotecan and temozolomide. Talazoparib will be given orally, days 1-6. Intravenous irinotecan and oral temozolomide will be given days 2-6. Filgrastim or peg-filgrastim will be given following the last dose of chemotherapy.
干预措施: Peg-filgrastim (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) of temozolomide combined with talazoparib
时间窗: After first cycle (21 days) therapy of patients of Arm B.
Once the MTD is defined for the combination of talazoparib plus irinotecan in Arm A, then temozolomide will be added to make a triple drug combination, talazoparib plus irinotecan and temozolomide. This is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib plus irinotecan and temozolomide. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan and temozolomide given daily on days 2-6.
Dose-limiting toxicities (DLT) of talazoparib combined with irinotecan
时间窗: After first cycle (21 days) therapy of patients of Arm A.
Dose-limiting toxicities defined in the first cycle of the combination of talazoparib and irinotecan will be summarized for patients treated at each dose level with DLTs type and grade.
Dose-limited toxicities (DLT) of combination therapy with temozolomide, talazoparib and irinotecan
时间窗: After first cycle (21 days) therapy of patients of Arm B.
DLT defined in the first cycle of the combination of talazoparib plus irinotecan and temozolomide will be summarized for patients treated at each dose level with DLTs type and grade.
Maximum tolerated dose (MTD) of talazoparib combined with irinotecan
时间窗: After first cycle (21 days) therapy of patients of Arm A.
This study is a traditional dose escalation study using a standard 3+3 phase I design to define the MTD. Six or more dose levels will be evaluated for the combination of talazoparib and irinotecan. Each cycle will last 21 days with talazoparib given daily on days 1-6 and irinotecan given daily on days 2-6.
次要结局
- Talazoparib AUC(days 1 and 5 (week 1) of course 1)
- Talazoparib Clearance(days 1 and 5 (week 1) of course 1)
- Irinotecan Tmax(days 1 and 5 (week 1) of course 1)
- Talazoparib Cmax(days 1 and 5 (week 1) of course 1)
- Response rate(After 34 cycles of therapy (approximate 24 months).)
- Irinotecan Cmax(days 1 and 5 (week 1) of course 1)
- Irinotecan AUC(days 1 and 5 (week 1) of course 1)
- Irinotecan Clearance(days 1 and 5 (week 1) of course 1)
- Talazoparib Tmax(days 1 and 5 (week 1) of course 1)
- Irinotecan t1/2(days 1 and 5 (week 1) of course 1)
- Talazoparib t1/2(days 1 and 5 (week 1) of course 1)