Talazoparib Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies
- Conditions
- Childhood Solid Tumors
- Interventions
- Registration Number
- NCT02392793
- Lead Sponsor
- St. Jude Children's Research Hospital
- Brief Summary
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.
- Detailed Description
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.
PRIMARY OBJECTIVES - ARM B
* To estimate the maximum tolerated dose (MTD) of temozolomide (given daily, days 2-6) when combined with talazoparib (daily, days 1-6) and 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 temozolomide, talazoparib and irinotecan administered in combination to patients with refractory or recurrent solid malignancies.
SECONDARY OBJECTIVES
* To estimate the response rate, within the confines of a phase I study, to talazoparib plus irinotecan and talazoparib plus irinotecan and temozolomide administered in combination in pediatric patients with refractory or recurrent solid malignancies.
* To characterize the pharmacokinetics of talazoparib plus irinotecan and talazoparib plus irinotecan and temozolomide when given in combination to children with refractory or recurrent solid malignancies.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 43
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: Talazoparib Plus Irinotecan Plus Temozolomide Peg-filgrastim 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. Arm A: Talazoparib Plus Irinotecan Talazoparib 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. Arm A: Talazoparib Plus Irinotecan 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. Arm A: Talazoparib Plus Irinotecan Peg-filgrastim 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. Arm A: Talazoparib Plus Irinotecan Filgrastim 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. Arm B: Talazoparib Plus Irinotecan Plus Temozolomide Talazoparib 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. Arm B: Talazoparib Plus Irinotecan Plus Temozolomide Irinotecan 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. Arm B: Talazoparib Plus Irinotecan Plus Temozolomide 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. Arm B: Talazoparib Plus Irinotecan Plus Temozolomide Filgrastim 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.
- Primary Outcome Measures
Name Time Method Maximum tolerated dose (MTD) of temozolomide combined with talazoparib 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 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 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 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.
- Secondary Outcome Measures
Name Time Method Talazoparib AUC days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Talazoparib Clearance days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Irinotecan Tmax days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Talazoparib Cmax days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Response rate After 34 cycles of therapy (approximate 24 months). We will provide summary statistics for the best overall response (complete response, partial response, stable disease and progressive disease) of patients experienced during treatment.
Irinotecan Cmax days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Irinotecan AUC days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Irinotecan Clearance days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Talazoparib Tmax days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Irinotecan t1/2 days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Talazoparib t1/2 days 1 and 5 (week 1) of course 1 A population average value and variance will be reported for week 1 of course 1
Trial Locations
- Locations (1)
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States