EGFR Gene Mutation, Glioblastoma, MGMT-Unmethylated Glioblastoma, Recurrent Glioblastoma
Conditions
Keywords
Immunotherapy, CAR T Therapy
Brief 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.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety of IV infused E-SYNC T cells for the treatment of EGFRvIII positive (EGFRvIII+) glioblastoma (GBM) (both cohorts). SECONDARY OBJECTIVES: I. To evaluate the feasibility of production and administration of E-SYNC T cells for the treatment of GBM (both cohorts). II. To determine the local priming of E-SYNC T cells by prospective evaluation of GBM tissue and peripheral blood (cohort 2 only). EXPLORATORY OBJECTIVES: I. To determine antitumor responses and survival after infusion of E-SYNC T cells. II. To evaluate development of immune responses against E-SYNC T cells favoring rejection. III. To characterize the intratumoral immune landscape. OUTLINE: This is a dose-escalation study utilizing E-SYNC T cells. COHORT 1 (Dose Escalation): An estimated 6 to 15 participants with newly diagnosed EGFRvIII+ glioblastoma with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated status who have completed initial radiation therapy will be assigned to cohort 1. Participants undergo leukapheresis for the creation of E-SYNC T cells at least 2 weeks after completion of their non-investigational, standard of care radiation therapy. COHORT 2 (Tissue Cohort): Five participants with EGFRvIII+ glioblastoma who have residual disease present and surgery is clinically appropriate will be assigned to cohort 2. Participants undergo leukapheresis for the creation of E-SYNC T cells more than 2 weeks after completion of their non-interventional, standard of care radiation therapy. Participants also undergo standard of care (SOC) surgical resection. After completion of study treatment, participants are followed up on days 1, 3, 7, 10, 14, 21, and 28, then every 4 weeks in weeks 8-24, every 8 weeks in weeks 32-48, every 12 weeks in weeks 60-96, every 3 months in months 24-36, and then annually in years 3-15. NOTE: The product formulation has been adjusted as of Protocol Version 2.1. Due to this formulation change, the first 3 participants enrolled at DL 1 prior to the adjustment will not be counted towards dose escalation analysis. These participants will continue for safety evaluation. Starting with the 4th participant, new enrollees will receive the updated formulation and continue to enroll at DL 1 to ensure consistency in dosing escalation decisions. The 4th participant will therefore serve as the 1st participant in updated DL1 cohort. Hence, enrollment will be paused after 4th participant is treated in updated DL1 formulation and monitoring and subsequent infusions will proceed per the staggered schedule
Interventions
BIOLOGICALE-SYNC T Cells
Given IV
DRUGCyclophosphamide (non-investigational)
Given IV
DRUGFludarabine (non-investigational)
Given IV
PROCEDURELeukapheresis
Undergo leukapheresis
PROCEDURESurgical resection
Undergo surgical resection of tumor tissue
Sponsors
Hideho Okada, MD, PhD
California Institute for Regenerative Medicine (CIRM)
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria for Cohort 1: 1. Age \>= 18 years. 2. Karnofsky performance status (KPS) score of \>=70. 3. All participants must have adequate organ function defined as: 1. Peripheral absolute neutrophil count \>=1000/mm\^3. 2. Platelet count \>=100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). 3. Absolute lymphocyte count (ALC) \>= 300/μL and/or Cluster of differentiation 3 (CD3) count of \>=150/μL. 4. Creatinine clearance or radioisotope glomerular filtration rate \>= 50 mL/min/1.73m\^2. 5. Total Bilirubin \<= 1.5 x ULN except for Gilbert's syndrome and 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 3x upper limit of normal (ULN). 7. Left ventricular ejection fraction (LVEF) \>= 50% by echocardiogram or multi-gated acquisition scanning (MUGA). 8. Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air. 4. Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel. 5. MGMT promoter must be unmethylated or with a methylation index \< 3. 6. Must have completed at least standard of care (SOC) external beam radiotherapy (EBRT) as initial therapy. 7. Participants must be anticipated to be able to complete E-SYNC T cell infusion within 12 weeks after completion of EBRT. 8. All participants must be off systemic steroids for 3 days or more prior to leukapheresis. 9. 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: 1. Age \>=18 years. 2. 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 1. Karnofsky Performance Scale (KPS) score \>=70. 2. 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. 3. Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII H-score of ≥ 150 based on central review. 4. Is surgically amenable, with expectation for ability to resect at least 500 mg of tumor tissue confirmed by participant's neurosurgeon. 5. 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. 6. Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test prior to receiving study interventions. 7. 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) 8. Must be willing to provide voluntary informed consent for study intervention.
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants reporting treatment-emergent adverse events | Up to 96 weeks | Treatment-emergent adverse events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants who successfully receive E-SYNC T cells | Up to 96 weeks | The percentage of participants for whom a sufficient quantity of drug product (E-SYNC T cells) could be manufactured from peripheral blood mononuclear cells (PBMC) obtained at apheresis and administered will be reported. |
| The percentage of primed E-SYNC T (Cohort 2 only) cells in TIL versus PBMC will be evaluated | Up to 96 weeks | The percentage of primed E-SYNC T cells in tumor-infiltrating lymphocytes (TIL) versus Peripheral blood mononuclear cell (PBMC) will be evaluated using single-cell RNA sequencing as a pilot study and described in 5 participants. |
Countries
United States
Contacts
CONTACTNeuro-Oncology New Patient Coordinator
STUDY_CHAIRJennifer Clarke, MD, MPH
University of California, San Francisco
Outcome results
None listed