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

• ClinicalTrials.gov Identifier: NCT05768880
• Recruitment Status: Not yet recruiting
• First Posted: March 15, 2023
• Last Update Posted: March 15, 2023
• Sponsor: Seattle Children's Hospital
• Information provided by (Responsible Party): Rebecca Gardner, Seattle Children's Hospital

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 (Clinical Trial)
• Estimated 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
• Estimated Study Start Date: April 25, 2023
• Estimated Primary Completion Date: January 15, 2028
• Estimated Study Completion Date: December 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

Outcome Measures

Primary Outcome Measures :

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

• Ages Eligible for Study: 1 Year to 26 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Nick Vitanza; 206-987-2106; CBDCIntake@seattlechildrens.org

Locations

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Sponsors and Collaborators

Seattle Children's Hospital

Investigators

• Study Chair: Nick Vitanza; Seattle Children's Hospital

More Information

• Responsible Party: Rebecca Gardner, Interim Chief Medical Officer, Seattle Children's Hospital
• ClinicalTrials.gov Identifier: NCT05768880
• Other Study ID Numbers: BrainChild-04
• First Posted: March 15, 2023
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

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 Rebecca Gardner, Seattle Children's Hospital:

CNS Tumor; DIPG; DMG; B7-H3; HER2; IL13-zetakine; EGFR806; CAR T cell; pediatric; brain tumor

Additional relevant MeSH terms:

Neoplasms; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Diffuse Intrinsic Pontine Glioma; Recurrence; Disease Attributes; Pathologic Processes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms by Site; Nervous System Diseases; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Brain Diseases; Central Nervous System Diseases