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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

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ClinicalTrials.gov Identifier: NCT04185038
Recruitment Status : Recruiting
First Posted : December 4, 2019
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
Julie Park, Seattle Children's Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
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 Biological: SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel Phase 1

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Study Type : Interventional
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 11, 2019
Estimated Primary Completion Date : May 2026
Estimated Study Completion Date : May 2041


Arm Intervention/treatment
Experimental: ARM A (Tumor Cavity Infusion)
Patients with non-DIPG supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity
Biological: SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
Autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3 specific chimeric antigen receptor (CAR) and EGFRt given via indwelling central nervous system (CNS) catheter

Experimental: ARM B (Ventricular System Infusion)
Patients with non-DIPG either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the ventricular system
Biological: SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
Autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3 specific chimeric antigen receptor (CAR) and EGFRt given via indwelling central nervous system (CNS) catheter

Experimental: ARM C (DIPG)
Patients with DIPG for whom CAR T cells will be delivered into the ventricular system
Biological: SCRI-CARB7H3(s); B7H3-specific chimeric antigen receptor (CAR) T cel
Autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3 specific chimeric antigen receptor (CAR) and EGFRt given via indwelling central nervous system (CNS) catheter




Primary Outcome Measures :
  1. 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 ]
    The type, frequency, severity, and duration of adverse events as a result of B7H3-specific CAR T cell infusion will be summarized

  2. Establish the feasibility, defined by the ability to produce and administer CAR T cell product, of B7H3-specific CAR T cell product infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system [ Time Frame: 28 days ]
    The proportion of products successfully manufactured and infused will be measured


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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

  3. 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 ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 26 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04185038


Contacts
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Contact: Nick Vitanza, MD 206-987-2106 CBDCIntake@seattlechildrens.org

Locations
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United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Nick Vitanza, MD    206-987-2106    CBDCIntake@seattlechildrens.org   
Principal Investigator: Nick Vitanza, MD         
Sponsors and Collaborators
Seattle Children's Hospital
Investigators
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Study Chair: Nick Vitanza, MD Seattle Children's Hospital
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Responsible Party: Julie Park, Medical Director, Immunotherapy Coordinating Center, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT04185038    
Other Study ID Numbers: BrainChild-03
First Posted: December 4, 2019    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Julie Park, Seattle Children's Hospital:
CNS, CAR T cell, B7-H3, pediatric, young adult, brain tumor, DIPG, DMG
Additional relevant MeSH terms:
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Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Rhabdoid Tumor
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Neoplasms, Complex and Mixed
Brain Neoplasms
Brain Diseases
Glioma
Ependymoma
Medulloblastoma
Pinealoma
Nervous System Diseases
Central Nervous System Diseases