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Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors

NCT04185038

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 B7H3-specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory CNS tumors. A child or young adult meeting all eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meeting none of the exclusion criteria, will have their T cells collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells. Patients will be assigned to one of 3 treatment arms based on location or type of their tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their treatment into the tumor cavity. Patients with either infratentorial or metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment delivered into the ventricular system. The first 3 patients enrolled onto the study must be at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned to Arm C and have their treatment delivered into the ventricular system. The patient's newly engineered T cells will be administered via the indwelling catheter for two courses. In the first course patients in Arms A and B 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. Patients in Arm C will receive a dose of CAR T cells every other week for 3 weeks, followed by a week off, an examination period, and then dosing every other week for 3 weeks. Following the two courses, patients in all Arms 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 B7H3-specific CAR T cells can be manufactured to complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can safely be administered through an indwelling CNS catheter or delivered directly into the brain via indwelling catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study. Secondary aims of the study will include evaluating 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 timepoints are available, also evaluate disease response to B7-H3 CAR T cell locoregional therapy.

Related Conditions:
  • Central Nervous System Neoplasm
  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors
  • Official Title: Phase 1 Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: BrainChild-03
  • NCT ID: NCT04185038

Conditions

  • Central Nervous System Tumor
  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma
  • Ependymoma
  • Medulloblastoma, Childhood
  • Germ Cell Tumor
  • Atypical Teratoid/Rhabdoid Tumor
  • Primitive Neuroectodermal Tumor
  • Choroid Plexus Carcinoma
  • Pineoblastoma, Childhood
  • Glioma

Interventions

DrugSynonymsArms
SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T celARM 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 B7H3-specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory CNS tumors. A child or young adult meeting all eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meeting none of the exclusion criteria, will have their T cells collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells. Patients will be assigned to one of 3 treatment arms based on location or type of their tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their treatment into the tumor cavity. Patients with either infratentorial or metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment delivered into the ventricular system. The first 3 patients enrolled onto the study must be at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned to Arm C and have their treatment delivered into the ventricular system. The patient's newly engineered T cells will be administered via the indwelling catheter for two courses. In the first course patients in Arms A and B 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. Patients in Arm C will receive a dose of CAR T cells every other week for 3 weeks, followed by a week off, an examination period, and then dosing every other week for 3 weeks. Following the two courses, patients in all Arms 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 B7H3-specific CAR T cells can be manufactured to complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can safely be administered through an indwelling CNS catheter or delivered directly into the brain via indwelling catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study. Secondary aims of the study will include evaluating 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 timepoints are available, also evaluate disease response to B7-H3 CAR T cell locoregional therapy.

Trial Arms

NameTypeDescriptionInterventions
ARM A (Tumor Cavity Infusion)ExperimentalPatients with non-DIPG supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity
  • SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
ARM B (Ventricular System Infusion)ExperimentalPatients with non-DIPG either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the ventricular system
  • SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
ARM C (DIPG)ExperimentalPatients with DIPG for whom CAR T cells will be delivered into the ventricular system
  • SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel

Eligibility Criteria

        Inclusion Criteria:

          -  First 3 enrolled subjects: age ≥ 15 and ≤ 26 years to Arm A or Arm B only Subsequent
             subjects: age ≥ 1 and ≤ 26 years and to Arms A, B, and C

          -  Diagnosis of refractory or recurrent CNS disease for which there is no standard
             therapy, or diagnosis of DIPG or DMG at any time point following completion of
             standard therapy

          -  Able to tolerate apheresis

          -  CNS reservoir catheter, such as an Ommaya or Rickham catheter

          -  Life expectancy ≥ 8 weeks

          -  Lansky or Karnofsky score ≥ 60

          -  Discontinued, and recovered from acute toxic effects of, all prior chemotherapy,
             immunotherapy, and radiotherapy

          -  Adequate organ function

          -  Adequate laboratory values

          -  Patients of childbearing/fathering potential must agree to use highly effective
             contraception

        Exclusion Criteria:

          -  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 >Grade 3 dysphagia

          -  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

          -  Subject and/or authorized legal representative unwilling or unable 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:Establish the safety, defined by the adverse events, of B7H3-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 7 months
Safety Issue:
Description:The type, frequency, severity, and duration of adverse events as a result of B7H3-specific CAR T cell infusion will be summarized

Secondary Outcome Measures

Measure:Assess the distribution of CNS-delivered B7H3-specific CAR T cells distribution within the cerebrospinal fluid (CSF) and peripheral blood
Time Frame:up to 6 months
Safety Issue:
Description:The trafficking of B7H3-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 B7H3-specific CAR T cells from the CSF into the peripheral blood will be evaluated.
Measure:Assessment of disease response of B7H3-expressing DIPG and DMG tumors to B7H3 specific CAR T cell therapy delivered into the tumor cavity or into the CNS
Time Frame:up to 6 months
Safety Issue:
Description:The response of DIPG and DMG tumors to B7H3-specific CAR T cell therapy delivered into the tumor cavity or into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs
Measure:Assessment of disease response of B7H3-expressing refractory or recurrent central nervous system (CNS) tumors to B7H3 specific CAR T cell therapy delivered into the tumor cavity or into the CNS
Time Frame:up to 6 months
Safety Issue:
Description:The response of refractory or recurrent CNS tumors to B7H3-specific CAR T cell therapy delivered into the tumor cavity or 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:Recruiting
Lead Sponsor:Seattle Children's Hospital

Trial Keywords

  • CNS, CAR T cell, B7-H3, pediatric, young adult, brain tumor, DIPG, DMG

Last Updated

December 2, 2019