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

Sponsor

Seattle Children's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05768880

Collaborator

(none)

Enrollment

Location

Arms

248.2

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma Recurrent CNS Tumor, Adult Recurrent, CNS Tumor, Childhood Refractory Primary Malignant Central Nervous System Neoplasm	Biological: SC-CAR4BRAIN	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Apr 25, 2023

Anticipated Primary Completion Date :

Jan 15, 2028

Anticipated Study Completion Date :

Dec 31, 2043

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Manufacturing Feasibility [42 days]
Number and percent of subjects with sufficient therapeutic product generated to receive two courses on the intended dose regimen
Safety of SC-CAR4BRAIN [28 days post-final SC-CAR4BRAIN infusion]
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
Dose level [28 days]
Establish the maximally tolerated dose regimen (MTDR) and recommended Phase 2 dose regimen (RP2DR) of fractionated intraventricular CNS administered SC CAR4BRAIN infusions.
Administration feasibility [98 days]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 26 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects must be age ≥ 1 and ≤ 26 years (except for the first 3 subjects, who must be age ≥ 12 and ≤ 26 years).
Subject disease classified as one of the following:
DIPG at any timepoint following completion of standard radiotherapy
DMG at any timepoint following completion of standard radiotherapy
Evidence of refractory or recurrent CNS disease for which there is no routine therapy, defined by either of the following:

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

Able to tolerate apheresis or already has an apheresis product available for use in manufacturing
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
Life expectancy ≥ 8 weeks
Lansky or Karnofsky score ≥ 60.
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.

Adequate organ function
Adequate laboratory values
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:

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 in the CNS
For Arm A subjects only: Presence of > Grade 3 dysphagia
Presence of active malignancy other than the CNS tumor under study
Presence of active severe infection, defined as either of the following:
Positive blood culture within 48 hours of enrollment, OR
Fever > 38.2ºC AND clinical signs of infection within 48 hours of enrollment
Pregnant or breastfeeding
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
Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol