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HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors

NCT03500991

Description:

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced to express a HER2-specific chimeric antigen receptor (CAR) and EGFRt, delivered by an indwelling catheter in the tumor resection cavity or ventricular system in children and young adults with recurrent or refractory HER2-positive CNS tumors. A child or young adult with a refractory or recurrent CNS tumor will have their tumor tested for HER2 expression by immunohistochemistry (IHC) at their home institution or at Seattle Children's Hospital. If the tumor is HER2 positive and the patient meets all other eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meets none of the exclusion criteria, then they can be apheresed, meaning T cells will be collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets HER2-expressing tumor cells. The patient's newly engineered T cells will then be administered via the indwelling CNS catheter for two courses. In the first course they will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Following the two courses, patient's will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving up to a total of six courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available. The hypothesis is that an adequate amount of HER2-specific CAR T cells can be manufactured to complete two courses of treatment with three doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that HER-specific CAR T cells safely can be administered through an indwelling CNS catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study safely can be delivered directly into the brain via indwelling catheter. Secondary aims of the study will include to evaluate CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple time points are available, also evaluate the degree of HER2 expression at diagnosis versus at recurrence.

Related Conditions:
  • Central Nervous System Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors
  • Official Title: Phase 1 Study of HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2 Positive Recurrent/Refractory Pediatric Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: BrainChild-01
  • NCT ID: NCT03500991

Conditions

  • Central Nervous System Tumor, Pediatric

Interventions

DrugSynonymsArms
HER2-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 lentivirally transduced to express a HER2-specific chimeric antigen receptor (CAR) and EGFRt, delivered by an indwelling catheter in the tumor resection cavity or ventricular system in children and young adults with recurrent or refractory HER2-positive CNS tumors. A child or young adult with a refractory or recurrent CNS tumor will have their tumor tested for HER2 expression by immunohistochemistry (IHC) at their home institution or at Seattle Children's Hospital. If the tumor is HER2 positive and the patient meets all other eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meets none of the exclusion criteria, then they can be apheresed, meaning T cells will be collected. The T cells will then be bioengineered into a third-generation CAR T cell that targets HER2-expressing tumor cells. The patient's newly engineered T cells will then be administered via the indwelling CNS catheter for two courses. In the first course they will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Following the two courses, patient's will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving up to a total of six courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available. The hypothesis is that an adequate amount of HER2-specific CAR T cells can be manufactured to complete two courses of treatment with three doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that HER-specific CAR T cells safely can be administered through an indwelling CNS catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study safely can be delivered directly into the brain via indwelling catheter. Secondary aims of the study will include to evaluate CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple time points are available, also evaluate the degree of HER2 expression at diagnosis versus at recurrence.

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 Intervention: HER2-specific chimeric antigen receptor (CAR) T cell
    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 Intervention: HER2-specific chimeric antigen receptor (CAR) T cell

      Eligibility Criteria

              Inclusion Criteria:
      
                -  First 3 enrolled subjects: age ≥ 15 and ≤ 26 years Subsequent subjects: age ≥ 1 and ≤
                   26 years
      
                -  Histologically diagnosed HER2-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 ≥ 60
      
                -  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 potential must agree to use highly effective contraception
      
              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 or unable to provide consent/assent for participation in the study and
                   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:15 Years
      Minimum Eligible Age:1 Year
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Establish the safety, defined by the adverse events, of HER2-specific CAR T cell infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system
      Time Frame:up to 6 months
      Safety Issue:
      Description:The type, frequency, severity, and duration of adverse events as a result of HER2-specific CAR T cell infusion will be summarized

      Secondary Outcome Measures

      Measure:Assess the distribution of CNS-delivered HER2-specific CAR T cells within the cerebrospinal fluid (CSF) and peripheral blood
      Time Frame:up to 6 months
      Safety Issue:
      Description:The trafficking of HER2-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 HER2-specific CAR T cells from the CSF into the peripheral blood will be evaluated
      Measure:Assessment of whether HER2 expression changes in relapsed CNS tumors that were HER2 positive prior to treatment with CAR T cells
      Time Frame:28 days
      Safety Issue:
      Description:The changes in HER2 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:Assessment of disease response of HER2-expressing refractory or recurrent central nervous system (CNS) tumors to HER2 specific CAR T cell therapy delivered directly into the CNS
      Time Frame:up to 6 months
      Safety Issue:
      Description:The response of recurrent or refractory central HER2-expressing CNS tumors to HER2-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, HER2-positive, brain tumor
      • pediatric, young adults

      Last Updated

      April 9, 2018