Study of B7-H3, EGFR806, HER2, And IL13-Zetakine (Quad) CAR T Cell Locoregional Immunotherapy For Pediatric Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, And Recurrent Or Refractory Central Nervous System Tumors

Phase 1 Study of B7-H3, EGFR806, HER2, And IL13-Zetakine (Quad) CAR T Cell Locoregional Immunotherapy For Pediatric Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, And Recurrent Or Refractory Central Nervous System Tumors

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with SC-CAR4BRAIN, an autologous CD4+ and CD8+ T cells lentivirally transduced to express to express combinations of B7-H3, EGFR806, HER2, and IL13-zetakine chimeric antigen receptors (CAR). CAR T cells are delivered via an indwelling catheter into the 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 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 target B7H3, EGFR806, HER2, and IL13-zetakine on tumor cells.

Patients will be assigned to 1 of 2 treatment Arms based on the type of their tumor:

• Arm A is for patients with DIPG (meaning primary disease localized to the pons, metastatic disease is allowed) anytime after standard radiation OR after progression.
• Arm B is for patients with non-pontine DMG (meaning DMG in other parts of the brain such as the thalamus or spine) anytime after standard radiation OR after progression. This Arm also includes other recurrent/refractory CNS tumors.

Study Overview

• Status: Recruiting
• Conditions: Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; Refractory Primary Malignant Central Nervous System Neoplasm; Recurrent CNS Tumor, Adult; Recurrent, CNS Tumor, Childhood
• Intervention / Treatment: Biological: SC-CAR4BRAIN

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rebecca Ronsley, MD; Phone Number: 206-987-2106; Email: CBDCIntake@seattlechildrens.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Rebecca Ronsley, MD; Phone Number: 206-987-2106; Email: CBDCIntake@seattlechildrens.org
      • Principal Investigator: Rebecca Ronsley, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 26 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects must be age ≥ 1 and ≤ 26 years (except for the first 3 subjects, who must be age ≥ 12 and ≤ 26 years).

2. Subject disease classified as one of the following:

   1. DIPG at any timepoint following completion of standard radiotherapy
   2. DMG at any timepoint following completion of standard radiotherapy
   3. Evidence of refractory or recurrent CNS disease for which there is no routine therapy, defined by either of the following:

   i. New site or sites of measurable or evaluable disease by radiographic imaging or histologic confirmation following completion of routine care first-line therapy for which curative salvage therapy is not available or amenable, OR ii. Measurable or evaluable disease that persists following completion of routine care first-line therapy for which curative salvage therapy is not available or amenable

3. Able to tolerate apheresis or already has an apheresis product available for use in manufacturing
4. CNS reservoir catheter, such as an Ommaya or Rickham catheter, present in the proper location for CNS-directed therapy delivered as specified for BrainChild-04
5. Life expectancy ≥ 8 weeks
6. Lansky or Karnofsky score ≥ 60.

7. If patient does not have previously obtained apheresis product, patient must have discontinued, and 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.
8. Adequate organ function
9. Adequate laboratory values
10. Subjects of childbearing/fathering potential must agree to use highly effective contraception from the time of enrollment through 12 months following the last T cell infusion

Exclusion Criteria:

1. Presence of ≥ Grade 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention
2. Presence of primary immunodeficiency/bone marrow failure syndrome
3. Presence of clinical and/or radiographic evidence of impending herniation in the CNS
4. For Arm A subjects only: Presence of > Grade 3 dysphagia
5. Presence of active malignancy other than the CNS tumor under study

6. Presence of active severe infection, defined as either of the following:

   1. Positive blood culture within 48 hours of enrollment, OR
   2. Fever > 38.2ºC AND clinical signs of infection within 48 hours of enrollment
7. Pregnant or breastfeeding
8. Subject and/or authorized legal representative unwilling to provide consent/assent for study participation, including participation in the 15-year follow-up period, which is required if CAR T cell therapy is administered
9. Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A - DIPG	Biological: SC-CAR4BRAIN; Courses of weekly intravenous SC-CAR4BRAIN infusions for 3 weeks, then 1 week off
Experimental: Arm B - DMG & recurrent/refractory tumors	Biological: SC-CAR4BRAIN; Courses of weekly intravenous SC-CAR4BRAIN infusions for 3 weeks, then 1 week off

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Manufacturing Feasibility	Number and percent of subjects with sufficient therapeutic product generated to receive two courses on the intended dose regimen	42 days
Safety of SC-CAR4BRAIN	Establish the safety, defined by the adverse events of fractionated intraventricular CNS administration of adoptive therapy with SC-CAR4BRAIN in children and young adults with DIPG, DMG, or recurrent/refractory CNS tumors	28 days post-final SC-CAR4BRAIN infusion
Dose level	Establish the maximally tolerated dose regimen (MTDR) and recommended Phase 2 dose regimen (RP2DR) of fractionated intraventricular CNS administered SC CAR4BRAIN infusions.	28 days
Administration feasibility	Number of subjects meeting criteria for their initial CAR T infusion and number of subjects meeting criteria for at least 2 courses of CAR T infusions	98 days

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Investigators: Principal Investigator: Rebecca Ronsley, MD, Seattle Children's Hospital; Study Chair: Rebecca Ronsley, MD, Seattle Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2023
• Primary Completion (Estimated): January 15, 2028
• Study Completion (Estimated): December 31, 2043

Study Registration Dates

• First Submitted: February 17, 2023
• First Submitted That Met QC Criteria: March 3, 2023
• First Posted (Actual): March 15, 2023

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: pediatric; HER2; CAR T cell; brain tumor; DIPG; B7-H3; DMG; CNS Tumor; IL13-zetakine; EGFR806
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Neoplasms; Recurrence; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Diffuse Intrinsic Pontine Glioma
• Other Study ID Numbers: BrainChild-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No