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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

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:

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:
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.
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

Sites / Locations

Seattle Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

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

NCT ID

NCT03638167

First Posted

August 15, 2018

Last Updated

January 18, 2023

Sponsor

Seattle Children's Hospital

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

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

Time Frame

up to 6 months

Title

Description

Time Frame

28 days

Title

Description

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

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

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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