CART-EGFR-IL13Ra2 cells for the Treatment of Newly Diagnosed, IDH Wild-Type, EGFR-Amplified, MGMT-Unmethylated Glioblastoma following Completion of Initial Radiotherapy

Inclusion Criteria

• STEP 1: Signed informed consent form
• STEP 1: Male or females age >= 18 years
• STEP 1: Patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma (as defined by World Health Organization [WHO] 2021 Classification for Central Nervous System [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)
• STEP 1: 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
• STEP 1: Tumor tissue positive for wild-type EGFR amplification by Neogenomics Laboratories
• STEP 1: Karnofsky performance status ≥ 60%
• STEP 1: Patient scheduled to receive 60 Gy of radiotherapy. Either photon or proton therapy is acceptable
• STEP 2: Patient completed full course of radiotherapy to 60 Gy
• STEP 2: No overt evidence of disease recurrence/progression post-radiotherapy confirmed by Response Assessment in Neuro-Oncology (RANO) 2.0 criteria
• STEP 2: Karnofsky performance status ≥ 60%
• STEP 2: Serum creatinine =< 1.5x upper limit of normal (ULN) or estimated creatinine clearance >= 30 mL/min and not on dialysis
• STEP 2: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 x institutional limit of normal (ILN)
• STEP 2: Total bilirubin ≤ 2.0 mg/dL, except for patients in whom hyperbilirubinemia is attributed to Gilbert’s syndrome (≤ 3.0 mg/dL)
• STEP 2: Left ventricular ejection fraction (LVEF) ≥ 45% confirmed by echocardiogram (ECHO)/multigated acquisition (MUGA)
• STEP 2: Must have minimum level of pulmonary reserve defined as > 92% on room air
• ELIGIBILITY FOR STUDY TREATMENT: Subjects must not have developed new disease complications, deterioration in performance status or overall clinical condition, new laboratory abnormalities, or new toxicities of therapy that would, in the opinion of the treating investigator, render it unsafe to proceed with study treatment
• ELIGIBILITY FOR STUDY TREATMENT: Subjects have adhered to all required restrictions
• ELIGIBILITY FOR STUDY TREATMENT: Subjects of child-bearing potential must not be pregnant as assessed by a negative serum pregnancy test drawn within 14 days prior to CART-EGFR-IL13Ra2 administration
• ELIGIBILITY FOR STUDY TREATMENT: Subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 14 days prior to CART-EGFR-IL13Ra2 administration. If the subject is positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving study treatment. The RVP does not need to be repeated prior to CAR T cell administration; however, if influenza signs and symptoms are present, study treatment should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, study treatment will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop; or longer if clinically appropriate for the respective viral pathogen. If clinical symptoms develop, study treatment will be delayed until resolution of these symptoms
• ELIGIBILITY FOR RETREATMENT: The subject has completed the Day 28 safety follow-up visit post-initial treatment with CART-EGFRIL13Ra2 cells
• ELIGIBILITY FOR RETREATMENT: The subject has experienced disease recurrence or progression following initial treatment with CART-EGFR-IL13Ra2 cells. This may be confirmed by RANO 2.0 criteria or be based on evidence of clinical progression as confirmed by a physician-investigator which necessitates use of alternative treatment (e.g., surgical intervention, etc.)
• ELIGIBILITY FOR RETREATMENT: Subjects must have a previously manufactured CART-EGFR-IL13Ra2 cell product available that meets the protocol-defined minimum acceptable dose, and a CSF-ventricular reservoir is still in place to allow for intracerebroventricular delivery
• ELIGIBILITY FOR RETREATMENT: Subjects must not have developed new disease complications, deterioration in performance status or overall clinical condition, new laboratory abnormalities, or new toxicities of therapy (either study treatment or alternative therapy) that would, in the opinion of the treating investigator, render it unsafe to proceed with the CART-EGFR-IL13Ra2 retreatment
• ELIGIBILITY FOR RETREATMENT: Subjects must have adhered to all required restrictions
• ELIGIBILITY FOR RETREATMENT: Participants of child-bearing potential must not be pregnant as assessed by a negative serum pregnancy test drawn within 14 days prior to CART-EGFR-IL13Ra2 retreatment
• ELIGIBILITY FOR RETREATMENT: Subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 14 days prior to CART-EGFR-IL13Ra2 retreatment. If the subject is positive f or influenza, Tamiflu® or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving the CAR T cells. The RVP does not need to be repeated prior to CAR T cell retreatment; however, if influenza signs and symptoms are present, CAR T cell retreatment should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, CAR T cell retreatment will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop; or longer if clinically appropriate for the respective viral pathogen. If clinical symptoms develop, CAR T cell retreatment will be delayed until resolution of these symptoms

Exclusion Criteria

• STEP 1: Active hepatitis B or hepatitis C infection
• STEP 1: Class III/IV cardiovascular disability according to the New York Heart Association Classification
• STEP 1: Tumors with enhancing disease involving the thalamus, brain stem or spinal cord
• STEP 1: Tumors with an MGMT promoter methylation result of hypermethylated, methylated, low positive methylated, or indeterminate
• STEP 1: Multifocal disease if >= 1 focus of tumor has not undergone maximal safe resection
• STEP 1: Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study
• STEP 1: History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
• STEP 1: Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to >= 10mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis [MS]) will be excluded
• STEP 1: 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: Any active, uncontrolled infection
• STEP 2: Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study
• STEP 2: Clinical or neurological decline related to disease and/or radiotherapy that, in the opinion of the physician-investigator, would preclude participation in this study
• STEP 2: Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods, as described in protocol
• STEP 2: Receipt of prior bevacizumab therapy for their newly diagnosed glioblastoma
• STEP 2: Receipt of temozolomide for their newly diagnosed glioblastoma
• STEP 2: Anticipated post-radiotherapy maintenance treatment that includes tumor treating fields, bevacizumab, or any other anti-neoplastic therapies
• STEP 2: Enrollment in any other clinical trial for the treatment of their newly diagnosed glioblastoma