CART-EGFR-IL13Ra2 in Newly Diagnosed GBM Following Initial Radiotherapy

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 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 IL13Ra2 (referred to as "CART-EGFR-IL13Ra2 cells") in patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma, without evidence of disease recurrence/progression following completion of initial radiotherapy.

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.