Clinical trial NCT06973096: CART-EGFR-IL13Ra2 in Newly Diagnosed GBM Following Initial Radiotherapy
Official title: Phase 1 Open-label Study Evaluating the Safety of CART-EGFR-IL13Rα2 Cells in Patients With Newly Diagnosed, EGFR-Amplified, MGMT-unmethylated Glioblastoma Following Completion of Initial Radiotherapy
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Glioblastoma
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2025-05-15
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is an open-label phase 1 study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 and IL3Ra2 (referred to as "CART-EGFR-IL13Ra2 cells"). Patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma who have undergone maximal safe surgical resection will be approached for initial study participation. A two-step screening/eligibility process will be utilized. Following informed consent, subjects who meet Step #1 Eligibility Criteria will remain on study and complete a course of radiotherapy (60 Gy) without temozolomide as per their routine cancer care. If there is no overt evidence of disease recurrence/progression following radiotherapy, additional screening tests/procedures will be performed. Subjects who then meet Step #2 Eligibility Criteria will undergo apheresis collection to initiate cell product manufacturing and surgical placement of a CSF-Ventricular Reservoir to allow for intracerebroventricular injection of the CART-EGFR-IL13Ra2 cells. All subjects will receive a single fixed dose of CART-EGFR-IL13Ra2 cells on Day 0 via intracerebroventricular delivery.


Eligibility criteria: Step #1 Inclusion Criteria:

1. Signed informed consent form
2. Male or females age ≥ 18 years.
3. Patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma (as defined by WHO 2021 Classification for CNS Tumors, including that the tumor must be IDH wildtype). The tumor must also have histopathologic evidence of glioblastoma (i.e., presence of microvascular proliferation and/or necrosis).
4. Patients must have undergone maximal safe resection of the tumor as per routine cancer care. Patients who have had a biopsy only are not eligible.
5. Tumor tissue positive for wild-type EGFR amplification by Neogenomics Laboratories
6. Karnofsky Performance Status ≥ 60%
7. Patient scheduled to receive 60 Gy of radiotherapy. Either photon or proton therapy is acceptable.

Step #1 Exclusion Criteria:

1. Active hepatitis B or hepatitis C infection
2. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
3. Tumors with enhancing disease involving the thalamus, brain stem or spinal cord.
4. Tumors with an MGMT promoter methylation result of hypermethylated, methylated, low positive methylated, or indeterminate.
5. Multifocal disease if ≥ 1 focus of tumor has not undergone maximal safe resection
6. Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
7. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
8. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
9. Anticipated treatment plan that involves bevacizumab, any other systemic anti-neoplastic therapy, and/or tumor-treating fields as part of 1st line therapy.

Step #2 Inclusion Criteria:

1. Patient completed full course of radiotherapy to 60 Gy.
2. No overt evidence of disease recurrence/progression post-radiotherapy confirmed by RANO 2.0 criteria.
3. Karnofsky Performance Status ≥ 60%
4. Adequate organ function defined as:

   1. Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 30 mL/min and not on dialysis
   2. ALT/AST ≤ 3 x ILN
   3. Total bilirubin ≤ 2.0 mg/dl, except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome (≤ 3.0 mg/Dl)
   4. Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
   5. Must have minimum level of pulmonary reserve defined as \> 92% on room air

Step #2 Exclusion Criteria:

1. Any active, uncontrolled infection.
2. Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
3. Clinical or neurological decline related to disease and/or radiotherapy that, in the opinion of the physician-investigator, would preclude participation in this study.
4. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
5. Receipt of prior bevacizumab therapy for their newly diagnosed glioblastoma.
6. Receipt of temozolomide for their newly diagnosed glioblastoma.
7. Anticipated post-radiotherapy maintenance treatment that includes tumor treating fields, bevacizumab, or any other anti-neoplastic therapies.
8. Enrollment in any other clinical trial for the treatment of their newly diagnosed glioblastoma.

Primary outcomes:
measure: Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0
timeFrame: Up to 15 years following CART-EGFR-IL13Ra2 administration
measure: Occurrence of treatment-limiting toxicities (TLTs)
timeFrame: 28 days post-CAR T cell administration
Secondary outcomes:
measure: Proportion of enrolled subjects who receive study treatment as planned
timeFrame: 28 days following initial treatment with CART-EGFR-IL13Ra2 cells
measure: Proportion of eligible subjects who receive study treatment as planned
timeFrame: 28 days following initial treatment with CART-EGFR-IL13Ra2 cells
measure: Frequency of manufacturing failures
timeFrame: 3 months
measure: Progression-free Survival (PFS)
timeFrame: Up to 15 years following CART-EGFR-IL13Ra2 administration
measure: Overall Survival (OS)
timeFrame: Up to 15 years following initial CART-EGFR-IL13Ra2 administration
measure: Objective Response Rate (ORR)
timeFrame: Up to 12 months following CART-EGFR-IL13Ra2 administration
measure: Duration of response (DOR)
timeFrame: Up to 15 years following initial CART-EGFR-IL13Ra2 administration
Other outcomes:
Locations:
Study officials:
affiliation: University of Pennsylvania
name: Stephen Bagley, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References: