Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma
- Conditions
- Recurrent Solid TumorRecurrent Ewing SarcomaRecurrent HepatoblastomaRecurrent NeuroblastomaRecurrent Malignant Germ Cell TumorRecurrent Peripheral Primitive Neuroectodermal TumorRefractory Malignant Germ Cell TumorRefractory Malignant Solid NeoplasmRefractory Peripheral Primitive Neuroectodermal TumorRecurrent Malignant Solid Neoplasm
- Interventions
- Registration Number
- NCT04901702
- Lead Sponsor
- St. Jude Children's Research Hospital
- Brief Summary
The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.
In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.
Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.
Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.
- Detailed Description
ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumors. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumor patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected.
Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.
Phase I Secondary Objectives
* To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
* To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
* To estimate the antitumor activity of Onivyde plus talazoparib and Onivyde plus temozolomide.
Phase I Exploratory Objectives
* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumors.
* To measure ctDNA at different time points and evaluate its relationship with response to therapy.
* To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.
Phase II Primary Objectives
• To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.
Phase II Secondary Objectives
* To describe the toxicity of the treatment regimens.
* To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
* To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
Phase II Exploratory Objectives
* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
* To describe ctDNA at different time points and the relationship with response to therapy.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.
Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumors who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation.
Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation.
Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumor cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumors (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 46
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description (Arm A) ONI plus TAL Talazoparib The phase I/II study will evaluate a treatment regimen; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) (Arm B) ONI plus TMZ Onivyde The phase I/II study will evaluate a treatment regimen; Onivyde (ONI) plus temozolomide (TMZ) (Arm A) ONI plus TAL Onivyde The phase I/II study will evaluate a treatment regimen; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) (Arm B) ONI plus TMZ Temozolomide The phase I/II study will evaluate a treatment regimen; Onivyde (ONI) plus temozolomide (TMZ)
- Primary Outcome Measures
Name Time Method Phase II:To estimate the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma. for five years following the date the last patient was randomized The study is designed to compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma. PFS is defined as the time from randomization to disease progression or death, whichever is earlier.
Phase I:To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies. approximately 21 days First cycle dose limiting toxicity (DLTs) will be used to determine the RP2Ds of the two treatment arms. The DLT is defined as any of the following events that are possibly, probably or definitely attributable to protocol therapy.
- Secondary Outcome Measures
Name Time Method To describe the antitumor activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B) At the end of treatment, up to 5 years after randomization of last participant Descriptive statistics of overall survival (OS) will be provided.
Phase I:To characterize the safety profile of the treatment regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B) At the end of treatment (up to 24 months after enrollment of last participant)] Safety and tolerability will consist of monitoring and recording all AEs and SAEs as characterized by type, frequency, severity, timing, seriousness and the relationship to the study therapy. These will be reported out qualitatively.
To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B) At the end of Cycle 1 (each cycle is 21 days) Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided For Onivyde: Vd on Day 1.
To estimate the antitumor activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B) At time of randomization until evaluation of respective endpoints, up to 2 years after enrollment of last participant Descriptive statistics of overall survival (OS) will be provided.
Phase II: To describe the toxicity of the treatment regimens. At the end of treatment (up to 24 months after enrollment of last participant) Safety and tolerability will consist of monitoring and recording all AEs and SAEs as characterized by type, frequency, severity, timing, seriousness and the relationship to the study therapy. These will be reported out qualitatively.
To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma. At the end of Cycle 1 (each cycle is 21 days) Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided For Onivyde: Vd on Day 1.
To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma At the end of cycle 1 (approximately 21 days after last participant enrollment) Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For Onivyde: area under the plasma concentration time curve (AUCinf) in Cycle 1.
Trial Locations
- Locations (10)
Lucille Packard Children's Hospital Stanford
🇺🇸Palo Alto, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Children's Healthcare of Atlanta/Emory University School of Medicine
🇺🇸Atlanta, Georgia, United States
Children's Hospital and Clinics of Minn
🇺🇸Minneapolis, Minnesota, United States
Texas Children's Hospital/ Baylor College of Medicine
🇺🇸Houston, Texas, United States
CHU Sainte-Justine
🇨🇦Montréal, Canada
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
BC Children's Hospital Research Institute
🇨🇦Vancouver, Canada
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States