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Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or Medulloblastoma

Primary Purpose

Ependymoma, Glioblastoma, Medulloblastoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ependymoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participant has verified leptomeningeal metastases
  • Participant must have a Karnofsky performance status (KPS) >= 60
  • Participant must have a life expectancy of >= 8 weeks
  • If participant has a ventriculoperitoneal shunt, the valve must be programmable, and must be able to tolerate their shunts being turned off for 48 hours
  • The effects of IL13Ralpha2-CAR T cells on a developing fetus are unknown. For this reason, women of child-bearing potential must have negative serum pregnancy test and agree to use a reliable form of birth control prior to study entry and for at least two months following study treatment. Male research participants must agree to use a reliable form of birth control and not donate sperm during the study and for at least two months following study treatment
  • Participant has a histologically confirmed IL13Ralpha2+ tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50)
  • Participant must have the ability to understand and the willingness to sign a written informed consent
  • No known contraindications to leukapheresis, steroids, or tocilizumab

Exclusion Criteria:

  • Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks
  • Research participant requires dialysis
  • Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy
  • Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase 1 study. A legal guardian may substitute for the research participant
  • Participant is unwilling to stop treatment with chemotherapy or endocrine therapy and/or radiation one week prior and during the first 4 cycles of the IL13Ralpha2-CAR T cell study
  • Shunted participants either have a non-programmable shunt valve, or cannot tolerate their shunts being turned off for 48 hours
  • Participant has a coagulopathy or bleeding disorder or cannot safely discontinue anticoagulation prior to placement of a Rickham reservoir
  • Participant has a chronic or active viral infection of the central nervous system (CNS)
  • Participant has any uncontrolled illness, including ongoing or active infection; participant has known active hepatitis B or C infection; participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
  • Participant is human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of signing the main informed consent
  • Participant has an autoimmune disease
  • Participant has another active malignancy
  • Participant is unable to undergo a brain magnetic resonance imaging (MRI)
  • Participant is pregnant or breast feeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IL13Ralpha2-CAR T cells, breastfeeding should be discontinued if the mother wants to participate in this study
  • Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Sites / Locations

  • City of Hope Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (IL13Ralpha2-CAR T cells)

Arm Description

Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of adverse events
Will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Overall survival
The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.

Secondary Outcome Measures

CAR T cell detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Endogenous T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Cell phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Cytokine levels in PB, TCF and CSF
Disease response
Measured by Response Assessment in Neuro-Oncology Criteria (RANO LM).
Time to progression
Progression defined by RANO LM criteria.
Overall survival
CAR T and endogenous cells detected in tumor tissue
Detected in tumor tissue by immunohistochemistry (IHC).
IL13Ralpha2 antigen expression levels in tumor tissue
Measured through the pathology H-score.
Biomathematical modeling of tumor growth
Will assess tumor growth parameter based on serial brain magnetic resonance imaging (MRI)s. Tumor volumes will be computed for each MRI study beginning with the pre-surgical MRI and will be used to compute growth rates, measured as change in tumor volume over time. Tumor volumes will be derived from T1- and T2-weighted MRI sequences. Growth rates will be compared prior to, during, and following CAR T-cell treatment for 1) each individual patient and 2) averaged for each dose level.
Biomathematical modeling of perfusion/diffusion
Will assess perfusion/ diffusion parameter based on serial brain magnetic resonance imaging (MRI)s. Perfusion and diffusion analysis will include the blood plasma-tissue rate transfer constant (Ktrans), cerebral blood volume (vp), contrast accumulation rate (lambda), and the apparent diffusion coefficient (ADC). Perfusion/diffusion analysis will be derived from T1-weighted dynamic contrast enhancement (DCE), T2-weighted dynamic susceptibility (DSC), and diffusion weighted imaging (DWI) sequences. The mean value of the perfusion/diffusion parameters from the contrast enhancing lesion volume will be extracted for each MRI study.

Full Information

First Posted
September 16, 2020
Last Updated
March 10, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04661384
Brief Title
Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or Medulloblastoma
Official Title
A Phase 1 Study to Evaluate IL13Rα2-Targeted Chimeric Antigen Receptor (CAR) T Cells for Adult Patients With Leptomeningeal Glioblastoma, Ependymoma or Medulloblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 5, 2021 (Actual)
Primary Completion Date
November 17, 2025 (Anticipated)
Study Completion Date
November 17, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial investigates the side effects of brain tumor-specific immune cells (IL13Ralpha2-CAR T cells) in treating patients with leptomeningeal disease from glioblastoma, ependymoma, or medulloblastoma. Immune cells are part of the immune system and help the body fight infections and other diseases. Immune cells can be engineered to destroy brain tumor cells in the laboratory. IL13Ralpha2-CAR T cells is brain tumor specific and can enter and express its genes in immune cells. Giving IL13Ralpha2-CAR T cells may better recognize and destroy brain tumor cells in patients with leptomeningeal disease from glioblastoma, ependymoma or medulloblastoma.
Detailed Description
PRIMARY OBJECTIVES: I. Examine and describe the safety and feasibility of IL13Ralpha2-specific hinge-optimized 41BB-co-stimulatory CAR truncated CD19-expressing autologous T-lymphocytes (IL13Ralpha2-CAR T cells) through intracerebroventricular (ICV) delivery as adjuvant therapy in participants with: Ia. IL13Ralpha2+ leptomeningeal disease from glioblastoma (arm 1). Ib. IL13Ralpha2+ leptomeningeal disease from ependymoma or medulloblastoma (arm 2). II. Determine the activity of IL13Ralpha2-CAR T cells based on survival rate at 3 months for both arms. SECONDARY OBJECTIVES: I. Describe persistence, expansion and phenotype of endogenous and IL13Ralpha2-CAR CAR T cells in peripheral blood (PB), tumor cyst fluid (TCF) and cerebral spinal fluid (CSF), when available. II. Describe cytokine levels in PB, TCF, and CSF (when available) over the study period for each arm. III. Estimate the rate of disease response by Response Assessment in Neuro-Oncology Leptomeningeal Metastases (RANO LM) criteria by study arm where an active response is defined as stable disease or better. IV. Estimate rate of progression free survival at 3 months by study arm. V. Estimate rate of overall survival (OS) at 3 months by study arm. VI. In study participants who undergo post therapy biopsy/resection or autopsy: VIa. Evaluate IL13Ralpha2-CAR T cell persistence in the tumor tissue and the location of the IL13Ralpha2-CAR T cells with respect to the infusion site. VIb. Evaluate IL13Ralpha2 antigen on tumor tissue pre- and post-CAR T cell therapy. VII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment. OUTLINE: Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles per the discretion of the principal investigator. After completion of study treatment, patients are followed up at 30 days, months 3, 6, 9, 12, and then yearly for up to 15 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ependymoma, Glioblastoma, Medulloblastoma, Recurrent Metastatic Malignant Neoplasm in the Leptomeninges

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (IL13Ralpha2-CAR T cells)
Arm Type
Experimental
Arm Description
Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Other Intervention Name(s)
Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells
Intervention Description
Given ICV
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time Frame
Up to 15 years
Title
Overall survival
Description
The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
Time Frame
At 3 months
Secondary Outcome Measure Information:
Title
CAR T cell detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Description
Measured by absolute number per ul by flow.
Time Frame
Up to 4 cycles (4 weeks)
Title
Endogenous T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Description
Measured by absolute number per ul by flow.
Time Frame
Up to 4 cycles (4 weeks)
Title
Cell phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Description
Measured by absolute number per ul by flow.
Time Frame
Up to 4 cycles (4 weeks)
Title
Cytokine levels in PB, TCF and CSF
Time Frame
Up to 4 cycles (4 weeks)
Title
Disease response
Description
Measured by Response Assessment in Neuro-Oncology Criteria (RANO LM).
Time Frame
Up to 15 years
Title
Time to progression
Description
Progression defined by RANO LM criteria.
Time Frame
Up to 15 years
Title
Overall survival
Time Frame
Up to 15 years
Title
CAR T and endogenous cells detected in tumor tissue
Description
Detected in tumor tissue by immunohistochemistry (IHC).
Time Frame
Baseline
Title
IL13Ralpha2 antigen expression levels in tumor tissue
Description
Measured through the pathology H-score.
Time Frame
Baseline
Title
Biomathematical modeling of tumor growth
Description
Will assess tumor growth parameter based on serial brain magnetic resonance imaging (MRI)s. Tumor volumes will be computed for each MRI study beginning with the pre-surgical MRI and will be used to compute growth rates, measured as change in tumor volume over time. Tumor volumes will be derived from T1- and T2-weighted MRI sequences. Growth rates will be compared prior to, during, and following CAR T-cell treatment for 1) each individual patient and 2) averaged for each dose level.
Time Frame
Up to 15 years
Title
Biomathematical modeling of perfusion/diffusion
Description
Will assess perfusion/ diffusion parameter based on serial brain magnetic resonance imaging (MRI)s. Perfusion and diffusion analysis will include the blood plasma-tissue rate transfer constant (Ktrans), cerebral blood volume (vp), contrast accumulation rate (lambda), and the apparent diffusion coefficient (ADC). Perfusion/diffusion analysis will be derived from T1-weighted dynamic contrast enhancement (DCE), T2-weighted dynamic susceptibility (DSC), and diffusion weighted imaging (DWI) sequences. The mean value of the perfusion/diffusion parameters from the contrast enhancing lesion volume will be extracted for each MRI study.
Time Frame
Up to 15 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participant has verified leptomeningeal metastases Participant must have a Karnofsky performance status (KPS) >= 60 Participant must have a life expectancy of >= 8 weeks If participant has a ventriculoperitoneal shunt, the valve must be programmable, and must be able to tolerate their shunts being turned off for 48 hours The effects of IL13Ralpha2-CAR T cells on a developing fetus are unknown. For this reason, women of child-bearing potential must have negative serum pregnancy test and agree to use a reliable form of birth control prior to study entry and for at least two months following study treatment. Male research participants must agree to use a reliable form of birth control and not donate sperm during the study and for at least two months following study treatment Participant has a histologically confirmed IL13Ralpha2+ tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50) Participant must have the ability to understand and the willingness to sign a written informed consent No known contraindications to leukapheresis, steroids, or tocilizumab Exclusion Criteria: Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks Research participant requires dialysis Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase 1 study. A legal guardian may substitute for the research participant Participant is unwilling to stop treatment with chemotherapy or endocrine therapy and/or radiation one week prior and during the first 4 cycles of the IL13Ralpha2-CAR T cell study Shunted participants either have a non-programmable shunt valve, or cannot tolerate their shunts being turned off for 48 hours Participant has a coagulopathy or bleeding disorder or cannot safely discontinue anticoagulation prior to placement of a Rickham reservoir Participant has a chronic or active viral infection of the central nervous system (CNS) Participant has any uncontrolled illness, including ongoing or active infection; participant has known active hepatitis B or C infection; participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections Participant is human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of signing the main informed consent Participant has an autoimmune disease Participant has another active malignancy Participant is unable to undergo a brain magnetic resonance imaging (MRI) Participant is pregnant or breast feeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IL13Ralpha2-CAR T cells, breastfeeding should be discontinued if the mother wants to participate in this study Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lisa A Feldman
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lisa A. Feldman
Phone
626-218-7293
Email
lfeldman@coh.org
First Name & Middle Initial & Last Name & Degree
Lisa A. Feldman

12. IPD Sharing Statement

Learn more about this trial

Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or Medulloblastoma

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