Phase 1 Study of Autologous Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13R alpha2 CAR (E-SYNC) T Cells in Adult Participants With EGFRvIII+ Glioblastoma
This phase I trial tests the safety, side effects, and best dose of E-SYNC chimeric antigen receptor (CAR) T cells after lymphodepleting chemotherapy in treating patients with EGFRvIII positive (+) glioblastoma. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so the CAR T cells will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Lymphodepleting chemotherapy with cyclophosphamide and fludarabine before treatment with CAR T cells may make the CAR T cells more effective.
• Inclusion Criteria for Cohort 1:
‣ Age \>= 18 years.
⁃ Karnofsky performance status (KPS) score of \>=70.
⁃ All participants must have adequate organ function defined as:
• Peripheral absolute neutrophil count \>=1000/mm\^3.
∙ Platelet count \>=100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
∙ Absolute lymphocyte count (ALC) \>= 300/μL and/or Cluster of differentiation 3 (CD3) count of \>=150/μL.
∙ Creatinine clearance or radioisotope glomerular filtration rate \>= 50 mL/min/1.73m\^2.
∙ Total Bilirubin \<= 1.5 x ULN except for Gilbert's syndrome and
∙ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 3x upper limit of normal (ULN).
∙ Left ventricular ejection fraction (LVEF) \>= 50% by echocardiogram or multi-gated acquisition scanning (MUGA).
∙ Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air.
⁃ Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel.
⁃ MGMT promoter must be unmethylated or with a methylation index \< 3.
⁃ Must have completed at least standard of care (SOC) external beam radiotherapy (EBRT) as initial therapy.
⁃ Participants must be anticipated to be able to complete E-SYNC T cell infusion within 12 weeks after completion of EBRT.
⁃ All participants must be off systemic steroids for 3 days or more prior to leukapheresis.
⁃ Must be willing to provide voluntary informed consent for apheresis (and tissue screening if needed) and for study treatment.
⁃ NOTE: There are two sets of eligibility criteria for Cohort 2. Tissue Screening: Defines eligibility for tissue screening and to determine H-score.
⁃ Study Enrollment: Defines eligibility for study enrollment and E-SYNC T cell manufacturing/treatment.
• Inclusion Criteria for Tissue Screening Cohort 2:
‣ Age \>=18 years.
⁃ Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel.
• Inclusion Criteria for Study Enrollment for Cohort 2
‣ Karnofsky Performance Scale (KPS) score \>=70.
⁃ received at least standard of care external beam radiotherapy (SOC EBRT) as initial therapy, with or without concurrent temozolomide (TMZ), and completed the last dose of TMZ ≥23 days prior to study enrollment). Note: patients may have initiated adjuvant TMZ +/- TTFields.
⁃ Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII H-score of ≥ 150 based on central review.
⁃ Is surgically amenable, with expectation for ability to resect at least 500 mg of tumor tissue confirmed by participant's neurosurgeon.
⁃ Participants with reproductive potential agree to use reliable and double barrier method of contraception during the study and for at least 6 months after the last study intervention, including refraining from donating sperm during this period.
⁃ Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test prior to receiving study interventions.
⁃ All participants must have adequate organ function.
‣ a. Adequate bone marrow function is defined as: i. Peripheral absolute neutrophil account ≥ 1000/mm3 and ii. Platelet count ≥ 100,000/mm3 (transfusion dependent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) and iii. Absolute lymphocyte count (ALC) ≥ 300/µL and/or CD3 count of ≥ 150/µL b. Adequate renal function is defined as: i. Creatinine clearance or radioisotope glomerular filtration rate ≥ 50 mL/min/1.73m2 c. Adequate liver function is defined as: i. Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for Gilbert's syndrome and ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN d. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) have to be within normal limits, unless the participant has been therapeutically anti-coagulated for previous venous thrombosis. e. Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air.
‣ f. Adequate cardiac function, confirmed within the last 12 months, defined as: i. Left ventricular ejection fraction (LVEF) ≥ 40% by echocardiogram or multi-gated acquisition scanning (MUGA)
⁃ Must be willing to provide voluntary informed consent for study intervention.