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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion 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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06973096
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University of Pennsylvania
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Stephen Bagley, MD, MSCE
Principal Investigator Affiliation	University of Pennsylvania
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastoma

Arms & Interventions

Arms

Experimental: Dose Level 1

Dose Level 1 (DL1): will receive single fixed dose of 2.5x10^7 CART-EGFR-IL13Ra2 cells via intracerebroventricular (ICV) injection on Day 0.

Experimental: Dose Level -1 (DL-1)

Dose Level-1 (DL-1): will receive single fixed dose of 1x10^7 CART-EGFR-IL13Ra2 cells via intracerebroventricular (ICV) injection on Day 0. This dose level will only be explored if there are at least two TLTs observed at DL1.

Interventions

Drug: - CART-EGFR-IL13Ra2 cells

autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR epitope 806 and a humanized scFv targeting IL13Ra2; both scFvs are fused to the 4-1BB and CD3ζ signaling domains.

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Abramson Cancer Center Clinical Trials Service

[email protected]

215-349-8245

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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