Intraventricular Infusion of T Cells Expressing B7-H3 Specific Chimeric Antigen Receptors (CAR) for the Treatment of Recurrent or Refractory Glioblastoma

Inclusion Criteria

• Age >= 18 years at the time of consent
• Karnofsky score of > 60%
• Diagnosis of supratentorial- or infra-tentorial GBM (World Health Organization [WHO] 2016 or 2021) or recurrent supratentorial- or infra-tentorial GBM (WHO 2016 or 2021) based on Response Assessment in Neuro-Oncology (RANO) MRI criteria. Disseminated GBM down the spinal cord is not allowed. Must have previously undergone resection or biopsy at initial diagnosis
• Must have undergone at least 4005 cGy of radiation with concurrent temozolomide
• No current or previous exposure to antiangiogenic agents, such as bevacizumab
• Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after study treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label.
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the cell infusion therapy. If a male subject receives multiple infusions, they must remain on contraception throughout the duration and 3 months after the last cell infusion therapy
• Subject is willing and able to comply with study procedures based on the judgement of the investigator
• Subject must not be pregnant or lactating (Note: breast milk cannot be stored for future use while the mother is being treated on study)
• Subjects must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Subjects must not have an active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused) * Note: To meet eligibility subjects are required to be negative for HIV antibody, negative for hepatitis B surface antigen, and negative for HCV antibody or viral load
• Subjects must not have a contraindication to MRI contrast agents or an inability to undergo MRI scans due to MRI non-compatible implanted materials
• Subjects must not have a prior exposure to chimeric antigen receptor T cell therapy for treatment of glioblastoma
• Subjects must not show evidence of disseminated disease involving the brainstem, cerebellum or spinal cord
• Subjects must not have previously implanted carmustine wafers or brachytherapy for the treatment of glioma
• PRIOR TO PROCUREMENT: Written informed consent to undergo cell procurement and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information explained to, understood by and signed by the subject or legally authorized representative
• PRIOR TO PROCUREMENT: Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to cell procurement. * Note: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• PRIOR TO PROCUREMENT: Hemoglobin (Hgb) >= 8 g/dL (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Platelets >= 100 x 10^9/L (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Creatinine =< 2 x upper limit of normal (ULN) (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Bilirubin =< 3 x upper limit of normal (ULN), unless attributed to Gilbert’s Syndrome (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Aspartate aminotransferase (AST) =< 5 x ULN (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Alanine aminotransferase (ALT) =< 5 x ULN (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Pulse oximetry >= 90 % on room air (within 7 days of cell procurement) * Note: Hematology and other lab parameters that are >= grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO PROCUREMENT: Subject has agreed to potentially have an intraventricular catheter placed in the intraventricular space for CAR.B7-H3 T cell infusions
• PRIOR TO PROCUREMENT: Subject has not received temozolomide within 48 hours of cell procurement
• PRIOR TO PROCUREMENT: Subject is not currently use of systemic corticosteroids at doses >= 2 mg dexamethasone daily or its equivalent; those receiving < 2 mg daily will be allowed if medically indicated prior to and following cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Written informed consent to undergo therapy with CAR.B7-H3 T cells explained to, understood by and signed by the subject or legally authorized representative; subject and/or legally authorized representative given a copy of informed consent form.
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Confirmed diagnosis of recurrent supratentorial or infratentorial GBM (WHO 2016 or 2021) based on RANO MRI criteria. Disseminated GBM down the spinal cord is not allowed
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Has at least ≥ 10 mm of measurable contrast-enhancing disease in a single dimension on MRI. Imaging results must be from within 10 days prior to CAR.B7-H3 T cell infusion and occur at least 2 weeks after most recent therapy (used as baseline measure for documentation of progression), with the exception of 50 mg/m 2 temozolomide (TMZ) where the MRI must occur at least 72 hours after TMZ bridging therapy, to document measurable disease
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Life expectancy >= 12 weeks
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Hemoglobin (Hgb) >= 8 g/dL (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Platelets >= 100 x 10^9/L (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Creatinine =< 2 x ULN (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Bilirubin =< 3 x upper limit of normal (ULN), unless attributed to Gilbert's Syndrome (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Aspartate aminotransferase (AST) =< 5 x ULN (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Alanine aminotransferase (ALT) =< 5 x ULN (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Pulse oximetry >= 90% on room air (within 72 hours prior to infusion) * Note: Hematology and other lab parameters that are =< grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject does not have rapidly progressive disease, per treating oncologist’s discretion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject is a good candidate for CAR-T cell therapy, per treating oncologist's discretion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Has a functional intraventricular catheter in place. Must be placed > 48 hours prior to initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject does not have a severe intercurrent infection or an unexplained febrile ( > 101.5°F) illness
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Available autologous transduced T lymphocytes that meet the Certificate of Analysis acceptance criteria
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received investigational therapy within 30 days of the initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received irinotecan within the 14 days of the initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received temozolomide 150-200 mg/m^2 within 14 days of the initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received temozolomide 50 mg/m^2 within 72 hours of the initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received loumustine within 21 days of the initial CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject has not received a checkpoint inhibitor within 30 days of CAR.B7-H3 T cell infusion
• PRIOR TO CAR.B7-H3 T CELL INFUSION: Subject does not have prior use of alternating tumor treating fields (Optune [registered trademark]) within 14 days of initial CAR.B7-H3 T cell infusion