Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ralpha2 CAR (E-SYNC) T Cells

NCT06186401 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 237045U19CA264338-03
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

EGFR Gene Mutation; Glioblastoma; MGMT-Unmethylated Glioblastoma; Recurrent Glioblastoma

Keywords

Immunotherapy; CAR T Therapy

Outcome Measures

Primary Outcomes (1)

• Proportion of participants reporting treatment-emergent adverse events

  Treatment-emergent adverse events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

  Up to 96 weeks

Secondary Outcomes (2)

• Percentage of participants who successfully receive E-SYNC T cells

  Up to 96 weeks

• The percentage of primed E-SYNC T (Cohort 2 only) cells in TIL versus PBMC will be evaluated

  Up to 96 weeks

Study Arms (3)

Cohort 1: Starting Dose Level 1 (5 x 10^7 CAR+ cells) (DL1)

EXPERIMENTAL

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.

Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2)

EXPERIMENTAL

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.

Biological: E-SYNC T Cells; Drug: Cyclophosphamide (non-investigational); Drug: Fludarabine (non-investigational); Procedure: Leukapheresis

Cohort 2: Tissue analysis cohort

EXPERIMENTAL

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.

Biological: E-SYNC T Cells; Drug: Cyclophosphamide (non-investigational); Drug: Fludarabine (non-investigational); Procedure: Leukapheresis; Procedure: Surgical resection

Interventions

E-SYNC T Cells BIOLOGICAL

Given IV

Also known as: Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13R alpha2 CAR T Cells, Autologous Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13R alpha2 CAR T Cells, Autologous Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ra2 CAR T Cells

Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2); Cohort 2: Tissue analysis cohort

Cyclophosphamide (non-investigational) DRUG

Given IV

Also known as: Cytoxan, Cytoxan Lyophilized, Neosar

Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2); Cohort 2: Tissue analysis cohort

Fludarabine (non-investigational) DRUG

Given IV

Also known as: Fludara, Oforta

Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2); Cohort 2: Tissue analysis cohort

Leukapheresis PROCEDURE

Undergo leukapheresis

Also known as: Therapeutic Leukopheresis

Cohort 1: Dose-escalation Level 2 (1.5 x 10^8 CAR+ cells) (DL2); Cohort 2: Tissue analysis cohort

Surgical resection PROCEDURE

Undergo surgical resection of tumor tissue

Also known as: Resection

Cohort 2: Tissue analysis cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Participant who has been treated with any investigational agents and chemotherapy targeting GBM \<= 4 weeks prior to date of study registration. Exceptions to this include: must be \>=23 days from last dose of temozolomide (TMZ) or radiotherapy, mush be \>= 6 weeks from last dose of nitrosourea.
• Female participants of reproductive potential who are pregnant or lactating. Female study participants of reproductive potential must have a negative serum pregnancy test as part of eligibility confirmation.
• Known addiction to alcohol or illicit drugs.
• Prior treatment with any Epithelial Growth Factor Receptor (EGFR)-targeting therapy.
• Participants with leptomeningeal dissemination.
• Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not excluded from the study.
• Participants with serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B surface antigen (HBsAg+) will be excluded. Participants that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. PCR positive participants will be excluded.
• Participants who have received prior solid organ or bone marrow transplantation.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, second cancer currently receiving active treatment or anticipated to receive treatment within the next year, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
• Participant who has been treated with any investigational agents or chemotherapy targeting GBM \<=4 weeks prior to date of study registration. Exceptions to this include: must be\>= 23 days from last dose of TMZ or radiotherapy, must be\>=6 weeks from last dose of nitrosourea.
• Female participants of reproductive potential who are pregnant or lactating. Female study participants of reproductive potential must have a negative serum pregnancy test as part of Step 1 eligibility confirmation.
• Uncontrolled active infection.
• Participants with a known disorder that affects their immune system, such as HIV or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy.
• Participants who are currently using non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not excluded from the study.

Sponsors & Collaborators

• California Institute for Regenerative Medicine (CIRM): collaborator
• National Cancer Institute (NCI): collaborator
• Hideho Okada, MD, PhD: lead

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

MeSH Terms

Conditions

Glioblastoma

Interventions

Cyclophosphamide; fludarabine; fludarabine phosphate; Leukapheresis

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Study Officials

• Jennifer Clarke, MD, MPH

  University of California, San Francisco

  STUDY CHAIR

Central Study Contacts

Neuro-Oncology New Patient Coordinator

CONTACT

877-827-3222; NeuroOncNewPatientCoord@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Co-Principal Investigator, IND Holder

Study Record Dates

• First Submitted: December 15, 2023
• First Posted: January 2, 2024
• Study Start: April 30, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 16, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)