Dual CAR T-cell therapy (EGFR-806 and IL13Ra2) after initial radiotherapy for newly diagnosed glioblastoma

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

This trial will test whether giving adults with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma a personalized dual CAR T-cell treatment after finishing initial radiotherapy is safe and shows early signs of benefit.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 9 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Pennsylvania (Academic / other)
• Drugs / interventions: bevacizumab, prednisone, CART
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT06973096 on ClinicalTrials.gov

What this trial studies

This open-label phase 1 trial gives participants autologous T cells engineered to co-express two chimeric antigen receptors that target a cryptic EGFR epitope (806) and IL13Ra2, following standard radiotherapy and surgical resection. Patients undergo lymphodepletion with fludarabine plus cyclophosphamide and may receive rituximab or a biosimilar as part of the regimen prior to CAR T-cell infusion. The primary focus is safety and feasibility, with secondary measures including pharmacokinetics and preliminary signs of anti-tumor activity. Eligible participants are adults with newly diagnosed, IDH-wildtype, EGFR-amplified, MGMT-unmethylated glioblastoma who have had maximal safe resection and completed planned radiotherapy.

Who should consider this trial

Good fit: Adults (age ≥18) with newly diagnosed, IDH-wildtype glioblastoma that is EGFR-amplified and MGMT-unmethylated, who had maximal safe resection (not biopsy only), KPS ≥60, and have completed initial radiotherapy are the intended candidates.

Not a fit: Patients with recurrent disease, non–EGFR-amplified or MGMT-methylated tumors, active hepatitis B or C, severe (NYHA class III/IV) cardiac disability, or who cannot undergo required procedures or travel to the site are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this targeted immune therapy could delay recurrence and potentially improve clinical outcomes for a subset of patients with EGFR-amplified, MGMT-unmethylated glioblastoma.

How similar studies have performed: Previous CAR T-cell approaches targeting IL13Ra2 or EGFR variants have produced occasional responses in glioblastoma but overall limited and variable results, making this dual-targeting approach novel and early-stage.

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.

Where this trial is running

Philadelphia, Pennsylvania

• University of Pennsylvania — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Stephen Bagley, MD, MSCE — University of Pennsylvania
• Study coordinator: Abramson Cancer Center Clinical Trials Service

Conditions Glioblastoma