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

• ClinicalTrials.gov Identifier: NCT03638167
• Recruitment Status: Recruiting
• First Posted: August 20, 2018
• Last Update Posted: February 25, 2020
• Sponsor: Seattle Children's Hospital
• Information provided by (Responsible Party): Julie Park, Seattle Children's Hospital

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.

Condition or disease	Intervention/treatment	Phase
Central Nervous System Tumor, Pediatric; Glioma; Ependymoma; Medulloblastoma; Germ Cell Tumor; Atypical Teratoid/Rhabdoid Tumor; Primitive Neuroectodermal Tumor; Choroid Plexus Carcinoma; Pineoblastoma	Biological: EGFR806-specific chimeric antigen receptor (CAR) T cell	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 Study of EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric Central Nervous System Tumors
• Actual Study Start Date: March 19, 2019
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: March 2037

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARM A (Tumor Cavity Infusion); Patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity	Biological: EGFR806-specific chimeric antigen receptor (CAR) T cell; 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
Experimental: ARM B (Ventricular System Infusion); 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	Biological: EGFR806-specific chimeric antigen receptor (CAR) T cell; 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

Outcome Measures

Primary Outcome Measures :

1. Safety: any adverse events associated with one or multiple EGFR806-specific CAR T cell product infusions will be assessed by CTCAE v5.0. [ Time Frame: up to 6 months ]
   The type, frequency, severity, and duration of adverse events as a result of EGFR806-specific CAR T cell infusion will be summarized
2. Feasibility: The number of successfully manufactured and infused EGFR806-specific CAR T cell product [ Time Frame: 28 days ]
   The proportion of products successfully manufactured and infused will be measured

Secondary Outcome Measures :

1. 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 [ Time Frame: up to 6 months ]
   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.
2. 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. [ Time Frame: 28 days ]
   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
3. 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. [ Time Frame: up to 6 months ]
   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.

Other Outcome Measures:

1. Quantitative biomarker assessment of anti tumor CAR T cell functional activity [ Time Frame: up to 6 months ]
   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 response by disease evaluations via CSF cytology and MRI imaging of the CNS.

Eligibility Criteria

• 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 Subsequent subjects: age ≥ 1 and ≤ 26 years
• Histologically diagnosed EGFR positive Central Nervous System (CNS) tumor
• Evidence of refractory or recurrent CNS disease that has failed first-line 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
• 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
• Subjects of childbearing/fathering potential must agree to use highly effective contraception
• Subject and/or authorized legal representative signed a written consent

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

Contacts and Locations

Contacts

Contact: Juliane Gust, MD, PhD; 206-987-2106; CBDCIntake@seattlechildrens.org

Contact: Nicholas Vitanza, MD; 206-987-2106; CBDCIntake@seattlechildrens.org

Locations

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Juliane Gust, MD, PhD

Contact: Nicholas Vitanza, MD

Principal Investigator: Juliane Gust, MD, PhD

Sponsors and Collaborators

Seattle Children's Hospital

Investigators

• Study Chair: Juliane Gust, MD, PhD; Seattle Children's Hospital

More Information

• Responsible Party: Julie Park, Medical Director, Immunotherapy Coordinating Center, Seattle Children's Hospital
• ClinicalTrials.gov Identifier: NCT03638167
• Other Study ID Numbers: BrainChild-02
• First Posted: August 20, 2018
• Last Update Posted: February 25, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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, EGFR-positive; pediatric, young adults, brain tumor

Additional relevant MeSH terms:

Neoplasms; Ependymoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Rhabdoid Tumor; Pinealoma; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Glioma; Neoplasms, Neuroepithelial; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms by Site; Nervous System Diseases; Neoplasms, Complex and Mixed; Brain Neoplasms; Brain Diseases; Central Nervous System Diseases