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

Status: Recruiting
Location: See location...
Intervention Type: Biological, Drug, Procedure
Study Type: Interventional
Study Phase: Phase 1
SUMMARY

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.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:

• 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) \>= 40% 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. Step 1 defines eligibility for tissue screening and apheresis, and Step 2 defines eligibility for study enrollment and E-SYNC T cell treatment.

• Inclusion Criteria for Cohort 2, Step 1:

‣ Age \>=18 years.

⁃ KPS score \>=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 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) \>= 40% 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, as defined by an EGFRvIII + H-score of \>=250 based on central review.

⁃ 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).

• Inclusion Criteria for Cohort 2, Step 2. Note: Prior to Step 2, participants must have undergone leukapheresis in Step 1. In addition:

‣ KPS score \>=70.

⁃ Must have received at least SOC EBRT as initial therapy; any number of prior recurrences is allowed.

⁃ Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII + H-score of \>=250 based on central review.

⁃ Must have radiographic progression consistent with the Response assessment in neuro-oncology criteria (RANO) criteria for progressive disease (PD)

⁃ Recurrence must be surgically amenable, with expectation for ability to resect at least 500mg of tumor tissue

⁃ 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 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 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).

∙ Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) have to be within normal limits, unless the participant has been therapeutically anticoagulated for previous venous thrombosis.

∙ Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air.

∙ Adequate cardiac function, confirmed within the last 12 months, defined as left ventricular ejection fraction (LVEF) \>= 40% by echocardiogram or multi-gated acquisition scanning (MUGA).

⁃ Must be willing to provide voluntary informed consent for apheresis (and tissue screening if needed).

Locations
United States
California
University of California, San Francisco
RECRUITING
San Francisco
Contact Information
Primary
Stephanie Lewis, MSN, RN
stephanie.lewis2@ucsf.edu
(415) 353-2193
Time Frame
Start Date: 2024-04-30
Estimated Completion Date: 2026-08-31
Participants
Target number of participants: 20
Treatments
Experimental: Cohort 1: Starting Dose Level 1 (5 x 10^7 CAR+ cells) (DL1)
Participants with newly diagnosed EGFRvIII+ GBM with unmethylated MGMT promotor status will undergo leukapheresis for manufacturing of E-SYNC T cells at least 2 weeks after completion of non-interventional, standard of care radiation therapy. Participants receive cyclophosphamide IV and fludarabine IV on days -5, -4, and -3 and then receive E-SYNC T cells IV on day 0. Participants will receive a single infusion of drug product (DP) (5 x 10\^7 CAR+ T cells) and be monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood.
Experimental: Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2)
If there are no dose-limiting toxicities in the starting dose cohort, participants with newly diagnosed EGFRvIII+ GBM with unmethylated MGMT promotor status will undergo leukapheresis for manufacturing of E-SYNC T cells at least 2 weeks after completion of tnon-interventional, standard of care radiation therapy. Participants receive cyclophosphamide IV and fludarabine IV on days -5, -4, and -3 and then receive E-SYNC T cells IV on day 0. Participants will receive a single infusion of drug product (DP) (1.5 x 10\^8 CAR+ T cells) and be monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood.
Experimental: Cohort 2: Tissue analysis cohort
Participants with EGFRvIII+ glioblastoma recurrence after initial non-investigational, chemoradiation who need surgery will have the EGFRvIII H-scored based on digital image analysis of EGFRvIII immunohistochemistry (IHC) slides, with the score denoting both extent of and intensity of positive staining. Participants with an H-score of \>=250 will undergo leukapheresis for manufacturing of E-SYNC T cells at the maximum tolerated dose, or recommended dose based on results from cohort 1 more than 2 weeks after completion of their non-investigational, standard of care radiation therapy. Participants will receive a single infusion of drug product (DP) on day 0 and will be admitted to the hospital for surgical resection (non-investigational) between days 14 and 28, and monitored for safety, presence of and possible synNotch \> CAR-T priming of the DP in the peripheral blood, and anti-tumor response of E-SYNC T cells.
Sponsors
Collaborators: California Institute for Regenerative Medicine (CIRM), National Cancer Institute (NCI)
Leads: Hideho Okada, MD, PhD

This content was sourced from clinicaltrials.gov

Similar Clinical Trials