Clinical Trials /

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

NCT04661384

Description:

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.

Related Conditions:
  • Ependymoma
  • Glioblastoma
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 19497
  • SECONDARY ID: NCI-2020-06010
  • SECONDARY ID: 19497
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT04661384

Conditions

  • Leptomeningeal Metastases

Interventions

DrugSynonymsArms
IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-LymphocytesAutologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T CellsTreatment (IL13Ralpha2-CAR T cells)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (IL13Ralpha2-CAR T cells)ExperimentalPatients 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.
  • IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Participant has treated leptomeningeal metastases after intrathecal chemotherapy
             and/or radiation OR refuses to undergo radiation and/or intrathecal chemotherapy

          -  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

        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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 15 years
Safety Issue:
Description:Will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:CAR T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Time Frame:Up to 4 cycles (4 weeks)
Safety Issue:
Description:Measured by absolute number per ul by flow.
Measure:Endogenous T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Time Frame:Up to 4 cycles (4 weeks)
Safety Issue:
Description:Measured by absolute number per ul by flow.
Measure:Cell phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Time Frame:Up to 4 cycles (4 weeks)
Safety Issue:
Description:Measured by absolute number per ul by flow.
Measure:Cytokine levels in PB, TCF and CSF
Time Frame:Up to 4 cycles (4 weeks)
Safety Issue:
Description:
Measure:Disease response
Time Frame:Up to 15 years
Safety Issue:
Description:Measured by Response Assessment in Neuro-Oncology Criteria (RANO LM).
Measure:Time to progression
Time Frame:Up to 15 years
Safety Issue:
Description:Progression defined by RANO LM criteria.
Measure:Overall survival
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:CAR T and endogenous cells detected in tumor tissue
Time Frame:Baseline
Safety Issue:
Description:Detected in tumor tissue by immunohistochemistry (IHC).
Measure:IL13Raphs2 antigen expression levels in tumor tissue.
Time Frame:Baseline
Safety Issue:
Description:Descriptive statistics will be provided.
Measure:Biomathematical Modeling of tumor growth
Time Frame:15 years
Safety Issue:
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.
Measure:Biomathematical Modeling of perfusion/diffusion
Time Frame:15 years
Safety Issue:
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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Trial Keywords

  • glioblastoma
  • ependymoma
  • meduloblastoma

Last Updated

December 10, 2020