CART-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM

Phase 1, Open-label Study Evaluating the Safety and Feasibility of CART-EGFR-IL13Ra2 Cells in Patients With EGFR-Amplified Recurrent Glioblastoma

This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 and IL13Ra2 (referred to as "CART-EGFR-IL13Ra2 cells") in patients with EGFR-amplified glioblastoma, IDH-wildtype that has recurred following prior radiotherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: CART-EGFR-IL13Ra2 Cells

Detailed Description

This is a Phase 1 study evaluating the safety and feasibility of CART-EGFR-IL13Ra2 cells in a 3+3 dose escalation design as described below.

• Cohort 1 (N = 3-6): will receive a single fixed dose of 1x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:

• If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
• If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Cohort 2.

In the event that 2 or more DLTs occur in Cohort 1, then enrollment into Cohort 1 will be stopped and the dose will be de-escalated to 5x10^6 CART-EGFR-IL13Ra2 cells. This de-escalated cohort will be identified as Cohort -1.

• Cohort -1 (N = 3-6): will receive a single fixed dose of 5x10^6 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:

• If 0 DLT/3 or 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
• If ≥ 2 DLTs occur at any time, enrollment onto this cohort will be stopped.

In the event of 0 DLT/3 subjects or 1 DLT/6 subjects in Cohort 1, then the study will advance to Cohort 2.

• Cohort 2 (N = 3-6): will receive a single fixed dose of 2.5x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:

  • If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
  • If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Cohort 3.
  • If 2 DLTs occur at any time, enrollment in this Cohort will be stopped. If less than 6 subjects were treated at the previous dose level (Cohort 1), additional subjects will be enrolled in that Cohort to reach a minimum of 6 evaluable subjects.

• Cohort 3 (N = 3-6): will receive a single fixed dose of 1x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:

  • If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
  • If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
  • If 2 DLTs occur at any time, enrollment in this Cohort will be stopped. If less than 6 subjects were treated at the previous dose level (Cohort 2), additional subjects will be enrolled in that Cohort to reach a minimum of 6 evaluable subjects.

The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 DLT occurs in 6 evaluable subjects.

The DLT observation period is 28 days post-initial treatment with CART-EGFR-IL13Ra2 cells (Day 0). In order to allow for appropriate monitoring/assessment of toxicities, the CART-EGFR-IL13Ra2 injections in the 1st and 2nd subjects in each cohort must be staggered by at least 28 days. If there are no emergent safety concerns identified in the first subject treated, subsequent subject injections within that same cohort do not need to be staggered and may occur sequentially (e.g. CART-EGFR-IL13Ra2 injections in the 2nd and 3rd subjects may occur in parallel without additional staggering requirements). Formal DLT evaluations will be performed after the 3rd subject in each cohort reaches the Day 28 safety follow-up visit, and will allow for a formal decision regarding cohort progression, expansion, or dose de-escalation. Formal DLT evaluations will be determined by the Clinical PI and Sponsor Medical Director in accordance with the definition in the protocol, Section 8.1.7.

Subjects must receive the target dose of CART-EGFR-IL13Ra2 cells as per their cohort assignment in order to be considered evaluable for dose escalation decisions and MTD determination. Subjects who do not receive the dose of CART-EGFR-IL13Ra2 cells as per their cohort assignment will not be considered evaluable for this purpose and will be replaced in this cohort. However, these subjects will still be included in the overall safety analysis, as well as the analyses of secondary and exploratory objectives.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed, written informed consent
2. Male or female age ≥ 18 years
3. Patients with glioblastoma, IDH-wildtype (as defined by WHO 2021 Classification of CNS Tumors) that has recurred following prior radiotherapy. For patients with tumors harboring methylation of the MGMT promoter, at least 12 weeks must have elapsed since completion of first-line radiotherapy.
4. Tumor tissue positive for wild-type EGFR amplification by NeoGenomics Laboratories. Archival tumor from patient's initial surgery at time of original diagnosis or recently collected tumor from time of recurrence are acceptable.
5. Surgical tumor resection for disease control/management or tumor biopsy to confirm tumor recurrence is clinically indicated in the opinion of the physician-investigator.

6. Adequate organ function defined as:

   1. Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 30 ml/min and not on dialysis.
   2. ALT/AST ≤ 3 x upper limit of normal range and total bilirubin ≤ 2.0 mg/dl, except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome (≤ 3.0 mg/dl).
   3. Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
   4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
7. Karnofsky Performance Status ≥ 60%.
8. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

1. Active hepatitis B or hepatitis C infection.
2. Any other active, uncontrolled infection.
3. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
4. Tumors primarily localized to the brain stem or spinal cord.
5. Severe, active co-morbidity in the opinion of the physician-investigator that would preclude participation in this study.
6. Receipt of bevacizumab within 3 months prior to physician-investigator confirmation of eligibility.
7. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg daily of prednisone. Patients with autoimmune neurological diseases (such as MS or Parkinson's) will be excluded.
8. Patients who are pregnant or nursing (lactating).
9. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Participants will receive a single fixed dose of 1x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.	Drug: CART-EGFR-IL13Ra2 Cells; autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2
Experimental: Cohort -1; Participants will receive a single fixed dose of 5x10^6 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.	Drug: CART-EGFR-IL13Ra2 Cells; autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2
Experimental: Cohort 2; Participants will receive a single fixed dose of 2.5x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.	Drug: CART-EGFR-IL13Ra2 Cells; autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2
Experimental: Cohort 3; Participants will receive a single fixed dose of 5x10^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.	Drug: CART-EGFR-IL13Ra2 Cells; autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2
Experimental: Cohort 4; Participants will receive a single dose of 2.5x107 CART-EGFR-IL13Ra2 cells given via intrathecal administration on Day 0, followed by a second dose of 2.5x107 CART-EGFR-IL13Ra2 cells given via intrathecal administration on Day 14 (+/-1d).	Drug: CART-EGFR-IL13Ra2 Cells; autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0	Type, frequency, severity, and attribution of adverse events	Up to 15 years following CART-EGFR-IL13Ra2 administration
Number of subjects with dose-limiting toxicities (DLTs)	Dose Escalation Phase only; Unacceptable toxicity as defined by the protocol	28 days following initial treatment with CART-EGFR-IL13Ra2 cells
Determination of maximum tolerated dose (MTD).	Dose Escalation Phase only: The maximum tolerated dose (MTD) is defined as the highest dose explored at which 0 or 1 DLT occurs in 6 evaluable subjects.	28 days following initial treatment with CART-EGFR-IL13Ra2 cellsnths
Determine the recommended dose for expansion (RDE).		Up to 12 months following initial treatment with CART-EGFR-IL13Ra2 cells
Proportion of eligible subjects who receive all planned doses of CART-EGFR-IL13Ra2 cells.	Cohort 4 only	28 days following initial treatment with CART-EGFR-IL13Ra2 cells

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of manufacturing failures	Proportion of subjects with CART-EGFR-IL13Ra2 products that fail to meet the product release criteria, out of the number of subjects in whom manufacturing was attempted. Proportion of subjects with CART-EGFR-IL13Ra2 products that fail to meet the assigned dose, out of the number of subjects in whom manufacturing was attempted.	3 months
Overall Survival (OS)	Time from initial study treatment to the date of death from any cause.	Up to 15 years following initial CART-EGFR-IL13Ra2 administration
Proportion of subjects who enroll on this study who received study treatment.	Evaluated based on the proportion of subjects who screen fail and those who receive any dose of CART-EGFR-IL13Ra2 cells.	12 months
Progression-Free Survival (PFS)	Per modified RANO criteria	Up to 15 years following CART-EGFR-IL13Ra2 administration
Objective Response Rate (ORR)	Per modified RANO criteria (in subjects with measurable disease at the time of study treatment); Proportion of subjects with confirmed CR and PR.	Up to 12 months following CART-EGFR-IL13Ra2 administration
Duration of response (DOR)	Per modified RANO criteria (in subjects with measurable disease at the time of study treatment); Time from the date when a response of confirmed CR/PR is first met to the date of confirmed disease progression, death or receipt of alternative treatment other than CART-EGFR-IL13Ra2 retreatment.	Up to 15 years following initial CART-EGFR-IL13Ra2 administration

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Kite Pharma (a Gilead Company)
• Investigators: Principal Investigator: Stephen Bagley, MD, MSCE, University of Pennsylvania

Publications and helpful links

General Publications

• Bagley SJ, Desai AS, Fraietta JA, Silverbush D, Chafamo D, Freeburg NF, Gopikrishna GK, Rech AJ, Nabavizadeh A, Bagley LJ, Park J, Jarocha D, Martins R, Sarmiento N, Maloney E, Lledo L, Stein C, Marshall A, Leskowitz RM, Jadlowsky JK, Mackey S, Christensen S, Oner BS, Plesa G, Brennan A, Gonzalez V, Chen F, Barrett D, Colbourn R, Nasrallah MP, Mourelatos Z, Hwang WT, Alanio C, Siegel DL, June CH, Hexner EO, Binder ZA, O'Rourke DM. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Ralpha2 in recurrent glioblastoma: a phase 1 trial. Nat Med. 2025 Aug;31(8):2778-2787. doi: 10.1038/s41591-025-03745-0. Epub 2025 Jun 1.
• Bagley SJ, Logun M, Fraietta JA, Wang X, Desai AS, Bagley LJ, Nabavizadeh A, Jarocha D, Martins R, Maloney E, Lledo L, Stein C, Marshall A, Leskowitz R, Jadlowsky JK, Christensen S, Oner BS, Plesa G, Brennan A, Gonzalez V, Chen F, Sun Y, Gladney W, Barrett D, Nasrallah MP, Hwang WT, Ming GL, Song H, Siegel DL, June CH, Hexner EO, Binder ZA, O'Rourke DM. Intrathecal bivalent CAR T cells targeting EGFR and IL13Ralpha2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med. 2024 May;30(5):1320-1329. doi: 10.1038/s41591-024-02893-z. Epub 2024 Mar 13.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2023
• Primary Completion (Estimated): December 19, 2039
• Study Completion (Estimated): December 19, 2039

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Cyclophosphamide; Fludarabine; Isotretinoin
• Other Study ID Numbers: 16321

Drug and device information, study documents

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