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

Primary Purpose

Central Nervous System Tumor, Pediatric, Glioma, Ependymoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
EGFR806-specific chimeric antigen receptor (CAR) T cell
Sponsored by
Seattle Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Central Nervous System Tumor, Pediatric focused on measuring CNS, CAR T cell, EGFR-positive, pediatric, young adults, brain tumor

Eligibility Criteria

1 Year - 26 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 15 and ≤ 26 years
  2. Histologically diagnosed EGFR positive Central Nervous System (CNS) tumor
  3. Evidence of refractory or recurrent CNS disease for which there is no standard therapy
  4. Able to tolerate apheresis or apheresis product available for use in manufacturing
  5. CNS reservoir catheter, such as an Ommaya or Rickham catheter
  6. Life expectancy ≥ 8 weeks
  7. Lansky or Karnofsky score ≥ 60
  8. If patient does not have previously obtained apheresis product, patient must have recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy and discontinue the following prior to enrollment:

    1. ≥ 7 days post last chemotherapy/biologic therapy administration
    2. 3 half lives or 30 days, whichever is shorter post last dose of anti-tumor antibody therapy
    3. Must be at least 30 days from most recent cellular infusion
    4. All systemically administered corticosteroid treatment therapy must be stable or decreasing within 1 week prior to enrollment with maximum dexamethasone dose of 2.5 mg/m2/day. Corticosteroid physiologic replacement therapy is allowed.
  9. Adequate organ function
  10. Adequate laboratory values
  11. Subjects of childbearing/fathering potential must agree to use highly effective contraception

Exclusion Criteria:

  1. Diagnosis of classic diffuse intrinsic pontine glioma (DIPG)
  2. Presence of ≥ Grade 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention
  3. Presence of primary immunodeficiency/bone marrow failure syndrome
  4. Presence of clinical and/or radiographic evidence of impending herniation
  5. Presence of active malignancy other than the primary CNS tumor under study
  6. Presence of active severe infection
  7. Receiving any anti-cancer agents or chemotherapy
  8. Pregnant or breastfeeding
  9. Subject and/or authorized legal representative unwilling to provide consent/assent for participation in the 15 year follow up period
  10. Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol

Sites / Locations

  • Seattle Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

ARM A (Tumor Cavity Infusion)

ARM B (Ventricular System Infusion)

Arm Description

Patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity

Patients with either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the fourth ventricle or lateral ventricle, respectively

Outcomes

Primary Outcome Measures

Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0.
The type, frequency, severity, and duration of adverse events as a result of EGFR806-specific CAR T cell infusion will be summarized
Feasibility: The number of successfully manufactured and infused EGFR806-specific CAR T cell product
The proportion of products successfully manufactured and infused will be measured

Secondary Outcome Measures

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
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.
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.
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
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.
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.

Full Information

First Posted
August 15, 2018
Last Updated
January 18, 2023
Sponsor
Seattle Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03638167
Brief Title
EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS Tumors
Official Title
Phase 1 Study of EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric Central Nervous System Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 19, 2019 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2040 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seattle Children's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Nervous System Tumor, Pediatric, Glioma, Ependymoma, Medulloblastoma, Germ Cell Tumor, Atypical Teratoid/Rhabdoid Tumor, Primitive Neuroectodermal Tumor, Choroid Plexus Carcinoma, Pineoblastoma
Keywords
CNS, CAR T cell, EGFR-positive, pediatric, young adults, brain tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ARM A (Tumor Cavity Infusion)
Arm Type
Experimental
Arm Description
Patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity
Arm Title
ARM B (Ventricular System Infusion)
Arm Type
Experimental
Arm Description
Patients 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 Type
Biological
Intervention Name(s)
EGFR806-specific chimeric antigen receptor (CAR) T cell
Intervention Description
Autologous CD4+ and CD8+ T cells lentivirally transduced to express an EGFR806 specific chimeric antigen receptor (CAR) and EGFRt given via indwelling central nervous system (CNS) catheter
Primary Outcome Measure Information:
Title
Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0.
Description
The type, frequency, severity, and duration of adverse events as a result of EGFR806-specific CAR T cell infusion will be summarized
Time Frame
up to 6 months
Title
Feasibility: The number of successfully manufactured and infused EGFR806-specific CAR T cell product
Description
The proportion of products successfully manufactured and infused will be measured
Time Frame
28 days
Secondary Outcome Measure Information:
Title
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
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.
Time Frame
up to 6 months
Title
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.
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
Time Frame
28 days
Title
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.
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.
Time Frame
up to 6 months
Other Pre-specified Outcome Measures:
Title
Quantitative biomarker assessment of anti tumor CAR T cell functional activity
Description
The presence of biomarkers of anti-tumor CAR T cell functional activity, such as cytokines, will be quantified via protein expression analysis in CSF. These findings will be correlated with safety determined by the occurrence of adverse events, and response by disease evaluations via CSF cytology and MRI imaging of the CNS.
Time Frame
up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
26 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 15 and ≤ 26 years Histologically diagnosed EGFR positive Central Nervous System (CNS) tumor Evidence of refractory or recurrent CNS disease for which there is no standard therapy Able to tolerate apheresis or apheresis product available for use in manufacturing CNS reservoir catheter, such as an Ommaya or Rickham catheter Life expectancy ≥ 8 weeks Lansky or Karnofsky score ≥ 60 If patient does not have previously obtained apheresis product, patient must have recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy and discontinue the following prior to enrollment: ≥ 7 days post last chemotherapy/biologic therapy administration 3 half lives or 30 days, whichever is shorter post last dose of anti-tumor antibody therapy Must be at least 30 days from most recent cellular infusion All systemically administered corticosteroid treatment therapy must be stable or decreasing within 1 week prior to enrollment with maximum dexamethasone dose of 2.5 mg/m2/day. Corticosteroid physiologic replacement therapy is allowed. Adequate organ function Adequate laboratory values Subjects of childbearing/fathering 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 Subject and/or authorized legal representative 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juliane Gust, MD, PhD
Organizational Affiliation
Seattle Children's Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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