HER2-specific Chimeric Antigen Receptor (CAR) T Cells for Children With Ependymoma
- Conditions
- Ependymoma
- Interventions
- Biological: HER2 Specific CAR T Cell
- Registration Number
- NCT04903080
- Lead Sponsor
- Pediatric Brain Tumor Consortium
- Brief Summary
This is a Phase I study to evaluate the safety profile of a type of immune therapy called HER2 CAR T cells (short for HER2 chimeric antigen receptor T cells). In addition to looking for side effects, we will study how well this treatment works against a brain tumor called ependymoma that has come back after treatment (recurrent) or has not responded well to treatment (progressive) in children. The HER2 CAR T cells used in this trial are made from the patient's own blood. A new gene, called the HER2 CAR, will be inserted into patient's T cells to allow them recognize a protein on the tumor called HER2. These HER2-specific CAR T cells may be able to target and kill ependymoma tumors that express HER2. This research is also studying how doable it is to provide this type of CAR T cell treatment to children being treated at different hospitals.
- Detailed Description
PBTC-059 is a multicenter, Phase I and Surgical study of the treatment HER2-specific CAR T cells for patients with refractory or recurrent ependymoma.
Phase I
The primary objectives of the Phase I study are to determine the safety of intravenous injection of HER2-specific CAR T cells after lymphodepleting chemotherapy, and to evaluate the multicenter feasibility of administering up to three infusions of HER2-CAR T cells after lymphodepletion.
Patients will receive one infusion of HER2psecific CAR T cells after lymphodepleting chemotherapy. Following recovery from their first treatment (no earlier than 8 weeks and no later than 12 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions after lymphodepleting chemotherapy if they meet laboratory parameters.
The length of time on study for patients enrolled on the Phase I study is anticipated to be 9 months on treatment. Patients will then be followed for 15 years after treatment.
Surgical Study
The objective of the Surgical study is to evaluate the post-treatment tumor tissue for presence of HER2-specific CAR T cells administered intravenously in children undergoing surgical resection. The surgical study will be initiated following completion of the safety evaluation period of 6 patients treated in the Phase I study.
Once the surgical study is open for enrollment, all patients who have clinical indication for surgery, except those needing urgent surgery, will be eligible for enrollment to the surgical study. Patients will receive one infusion of HER2-specific CAR T cells after lymphodepleting chemotherapy 4-6 weeks before surgical resection of their tumor, at which time samples will be taken for analysis. Following recovery from surgery (no earlier than 8 weeks and no later than 15 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions if they meet laboratory parameters.
The first patient in the surgical study will complete a 6-week safety evaluation period prior to enrollment of the subsequent patient. The length of time on study for patients enrolled on the Surgical study is anticipated to be 10 months on treatment. Patients will then be followed for 15 years after treatment.
Dosing
All patients on Phase I and Surgical study will receive HER2 CAR T cells at a patient-specific dose level 1 (8x10\^7 CAR-positive T cells/m\^2) for infusion. The cell dose will be based on the patient weight and height obtained by the treating institution at the time of procurement. For patients whose BMI is greater than 95th percentile for given age and sex, the Body surface area (BSA) will be calculated using the ideal body weight.
In the event that dose level 1 is found to have excessive toxicity, three additional doses of CAR T cells at dose level -1 (5x10\^7 CAR-positive T cells/m\^2) will be made to be used in the event that dose de-escalation occurs before a patient is enrolled for treatment.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment (HER2 CAR T cells), Phase I Arm HER2 Specific CAR T Cell Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0. Treatment repeats every 8 to 12 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity. Treatment (HER2 CAR T cells), Surgical Arm HER2 Specific CAR T Cell Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0 followed by surgical tumor resection 4-6 weeks following HER2 CAR T cell infusion. Treatment repeats every 8 to 15 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Number of Subjects with Dose-Limiting Toxicity (DLT) in Phase I Arm Up to 42 days following the first CAR T cell infusion DLT is defined as an adverse event that is at least possibly attributed to the investigational agent (HER2 CAR T cells) that occurs during the dose-finding period (the first 42 days following the first CAR T cell infusion) regardless of expectedness with a few exceptions, for which Section 6.4 of the protocol provides more details. All patients in Safety/Feasibility cohort who received at least 1 dose of HER2 CAR T cells are included in the assessment.
Number of Subjects with Dose-Limiting Toxicity (DLT) in Surgical Arm Up to 42 days following the first CAR T cell infusion DLT is defined as an adverse event that is at least possibly attributed to the investigational agent (HER2 CAR T cells) that occurs during the dose-finding period (the first 42 days following the first CAR T cell infusion) regardless of expectedness with a few exceptions, for which Section 6.4 of the protocol provides more details. All patients in Surgical cohort who received at least 1 dose of HER2 CAR T cells are included in the assessment.
Percentage of Subjects whose Treatment Delivery Meets Feasibility Criteria Approximately 3 months after enrollment for treatment Assessment of feasibility is in the context of conducting an investigator-initiated (not industry sponsored) multi-institutional trial of CAR T cells. This would specifically include the feasibility of manufacturing the cells at one center and shipping them to other sites for administration and the infusion process. If more than 25% of patients cannot be treated as intended due to manufacturing, shipping or administration related causes (jointly considered as feasibility criteria), this would be considered unacceptable. If the treatment is not delivered as intended due to one or more manufacturing, shipping, or administration related causes, this instance will be counted as feasibility failure for that subject.
- Secondary Outcome Measures
Name Time Method Presence of intra-tumoral HER2 CAR T Cells following First Infusion in Surgical Arm Approximately 3 months after enrollment for treatment Frequency of HER2-specific CAR T cells is measured at first infusion in subjects in Surgical cohort. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Expansion and Persistence of HER2 CAR T Cells at First Infusion in patients who received this treatment Approximately 3 months after enrollment for treatment Frequency of HER2-specific CAR T cells is measured at first infusion in treated subjects. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Presence of HER2 CAR T Cells following Third Infusion in Surgical Arm Approximately 9 months after enrollment for treatment Frequency of HER2-specific CAR T cells is measured at third infusion in subjects in Surgical cohort. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Event-free Survival (EFS) Up to 2 years from the initiation of protocol treatment 2-year EFS is estimated for all eligible subjects who initiated the conditioning regimen. EFS is defined as the time interval between date of initiation of protocol treatment and minimum date of documentation of disease progression, second malignancy, death due to any cause, or date of last follow-up.
Expansion and Persistence of HER2 CAR T Cells at Third Infusion in patients who received this treatment Approximately 10 months after enrollment for treatment Frequency of HER2-specific CAR T cells is measured at third infusion in treated subjects. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Best antitumor Response of Infused HER2 CAR T Cells in Phase I Arm Up to 15 years from the initiation of protocol treatment Proportion of subjects with complete response (CR) or partial response (PR) is calculated. Patients in Safety/Feasibility cohort who received at least 1 dose of CAR T cells are considered. CR refers to complete resolution of all evaluable tumor and mass effect maintained for at least 4 weeks. PR refers to for measurable disease a greater than or equal to 50% reduction in tumor size by bi-dimensional measurement maintained for at least 4 weeks.
Best Antitumor Response of Infused HER2 CAR T Cells in Surgical Arm Up to 15 years from the initiation of protocol treatment Proportion of subjects with complete response (CR) or partial response (PR) or clinical complete response (CCR) is calculated. Patients in Surgical cohort who received at least 1 dose of CAR T cells are considered. CR refers to complete resolution of all evaluable tumor and mass effect maintained for at least 4 weeks. PR refers to for measurable disease a greater than or equal to 50% reduction in tumor size by bi-dimensional measurement maintained for at least 4 weeks. CR and PR are for subjects with measurable disease. CCR is for subjects who do not have measurable disease.
Expansion and Persistence of HER2 CAR T Cells at Second Infusion in patients who received this treatment Approximately 7 months after enrollment of treatment Frequency of HER2-specific CAR T cells is measured at second infusion in treated subjects. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Presence of HER2 CAR T Cells following Second Infusion in Surgical Arm Approximately 6 months after enrollment for treatment Frequency of HER2-specific CAR T cells is measured at second infusion in subjects in Surgical cohort. Data are summarized at pre- and post-infusion time points to evaluate their expansion and persistence.
Overall Survival (OS) 2 years from the initiation of protocol treatment 2-year OS is estimated for all eligible subjects who initiated the conditioning regimen. OS is defined as the time interval between date of initiation of protocol treatment and date of death due to any cause or date of last follow-up.
Trial Locations
- Locations (5)
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Pittsburgh Children's Hospital of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Texas Children's Cancer Center
🇺🇸Houston, Texas, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States