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EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS Tumors

NCT03638167

Description:

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells that are lentivirally transduced to express an EGFR806 specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or the ventricular system in children and young adults with recurrent or refractory EGFR-positive CNS tumors. The primary objectives of this protocol are to evaluate the feasibility, safety, and tolerability of CNS-delivered fractionated CAR T cell infusions employing intra-patient dose escalation. Subjects with supratentorial tumors will receive sequential EGFR806-specific CAR T cells delivered into the tumor resection cavity, subjects with infratentorial tumors will receive sequential CAR T cells delivered into the fourth ventricle, and subjects with leptomeningeal disease will receive sequential CAR T cells delivered into the lateral ventricle. The secondary objectives are to assess CAR T cell distribution within the cerebrospinal fluid (CSF), the extent to which CAR T cells egress into the peripheral circulation, and EGFR expression at recurrence of initially EGFR-positive tumors. Additionally, tumor response will be evaluated by magnetic resonance imaging (MRI) and CSF cytology. The exploratory objectives are to analyze CSF specimens for biomarkers of anti-tumor CAR T cell presence and functional activity.

Related Conditions:
  • Malignant Central Nervous System Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS Tumors
  • Official Title: Phase I Study of EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: BrainChild-02
  • NCT ID: NCT03638167

Conditions

  • Central Nervous System Tumor, Pediatric

Interventions

DrugSynonymsArms
EGFR806-specific chimeric antigen receptor (CAR) T cellARM A (Tumor Cavity Infusion)

Purpose

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells that are lentivirally transduced to express an EGFR806 specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or the ventricular system in children and young adults with recurrent or refractory EGFR-positive CNS tumors. The primary objectives of this protocol are to evaluate the feasibility, safety, and tolerability of CNS-delivered fractionated CAR T cell infusions employing intra-patient dose escalation. Subjects with supratentorial tumors will receive sequential EGFR806-specific CAR T cells delivered into the tumor resection cavity, subjects with infratentorial tumors will receive sequential CAR T cells delivered into the fourth ventricle, and subjects with leptomeningeal disease will receive sequential CAR T cells delivered into the lateral ventricle. The secondary objectives are to assess CAR T cell distribution within the cerebrospinal fluid (CSF), the extent to which CAR T cells egress into the peripheral circulation, and EGFR expression at recurrence of initially EGFR-positive tumors. Additionally, tumor response will be evaluated by magnetic resonance imaging (MRI) and CSF cytology. The exploratory objectives are to analyze CSF specimens for biomarkers of anti-tumor CAR T cell presence and functional activity.

Trial Arms

NameTypeDescriptionInterventions
ARM A (Tumor Cavity Infusion)ExperimentalPatients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity
    ARM B (Ventricular System Infusion)ExperimentalPatients with either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the fourth ventricle or lateral ventricle, respectively

      Eligibility Criteria

              Inclusion Criteria:
      
                -  First 3 enrolled subjects: age ≥ 15 and ≤ 26 years Subsequent subjects: age ≥ 1 and ≤
                   26 years
      
                -  Histologically diagnosed EGFR positive Central Nervous System (CNS) tumor
      
                -  Evidence of refractory or recurrent CNS disease that has failed first-line therapy
      
                -  Willing and able to provide tumor specimens
      
                -  Able to tolerate apheresis
      
                -  Functional CNS reservoir catheter, such as an Ommaya or Rickham catheter
      
                -  Life expectancy ≥ 8 weeks
      
                -  Lansky or Karnofsky score ≥ 50
      
                -  Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and
                   radiotherapy
      
                -  ≥ 7 days post last chemotherapy administration
      
                -  3 half lives or 30 days, whichever is shorter post last dose of anti-tumor antibody
                   therapy
      
                -  No prior virotherapy. Prior genetically modified cell therapy is allowed if not
                   detectable at enrollment.
      
                -  Stable or decreasing dosing of steroid treatment for symptomatic relief from CNS
                   disease, with maximum dexamethasone dose of 2.5 mg/m2/day
      
                -  Adequate organ function
      
                -  Adequate laboratory values
      
                -  Patients of childbearing/fathering potential must agree to use highly effective
                   contraception
      
                -  Signed a written consent
      
              Exclusion Criteria:
      
                -  Diagnosis of classic diffuse intrinsic pontine glioma (DIPG)
      
                -  Presence of ≥ Grade 3 cardiac dysfunction or symptomatic arrhythmia requiring
                   intervention
      
                -  Presence of primary immunodeficiency/bone marrow failure syndrome
      
                -  Presence of clinical and/or radiographic evidence of impending herniation
      
                -  Presence of active malignancy other than the primary CNS tumor under study
      
                -  Presence of active severe infection
      
                -  Receiving any anti-cancer agents or chemotherapy
      
                -  Pregnant or breastfeeding
      
                -  Unwilling to provide consent/assent for participation in the 15 year follow up period
      
                -  Presence of any condition that, in the opinion of the investigator, would prohibit the
                   patient from undergoing treatment under this protocol
            
      Maximum Eligible Age:26 Years
      Minimum Eligible Age:1 Year
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0.
      Time Frame:up to 6 months
      Safety Issue:
      Description:The type, frequency, severity, and duration of adverse events as a result of EGFR806-specific CAR T cell infusion will be summarized

      Secondary Outcome Measures

      Measure:CAR T cell distribution: The number of subjects with CAR T cell persistence in the cerebrospinal fluid (CSF) and peripheral blood as measured by flow cytometry
      Time Frame:up to 6 months
      Safety Issue:
      Description:The trafficking of the EGFR806-specific CAR T cell product through the CSF by measuring remaining CAR T cells from a prior infusion at the time of each infusion and the trafficking of EGFR806-specific CAR T cells from the CSF into the peripheral blood will be evaluated.
      Measure:Expression of target epitope: assessment of whether EGFR expression changes in relapsed CNS tumors that were EGFR positive prior to treatment with CAR T cells via immunohistochemistry on resected tissue samples.
      Time Frame:28 days
      Safety Issue:
      Description:The changes in EGFR expression at diagnosis and recurrence of central nervous system (CNS) tumors, if samples from multiple time points is available, will be investigated by evaluating pathology specimens from previous surgeries
      Measure:Disease response: Assessment of disease response of EGFR-expressing refractory or recurrent central nervous system (CNS) tumors to EGFR806 specific CAR T cell therapy delivered directly into the CNS by cytology and radiology criteria.
      Time Frame:up to 6 months
      Safety Issue:
      Description:The response of recurrent or refractory central EGFR-expressing CNS tumors to EGFR806-specific CAR T cell therapy delivered directly into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs.

      Details

      Phase:Phase 1
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:Seattle Children's Hospital

      Trial Keywords

      • CNS, CAR T cell, EGFR-positive
      • pediatric, young adults, brain tumor

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