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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) (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.

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.

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.

E-SYNC T Cells

Cyclophosphamide (non-investigational)

Fludarabine (non-investigational)

Leukapheresis

Undergo surgical resection of tumor tissue

Surgical resection

Stephanie Lewis, MSN, RN

Jennifer Clarke, MD, MPH

Hideho Okada, MD, PhD

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.

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: 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: Participants with EGFRvIII+ glioblastoma recurrence after initial chemoradiation who need surgery are 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.

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

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

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

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.

Success will be defined as at least 2 of the 5 (or 8) participants having an increase in primed E-SYNC T cells in tumor-infiltrating lymphocytes (TIL)vs PBMC of \>= 15%

California Institute for Regenerative Medicine (CIRM)

National Cancer Institute (NCI)

Co-Principal Investigator, IND Holder

Blood and Lymph Conditions

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Acute Graft Versus Host Disease

Autologous hematopoietic stem cells (aHSCs) infused on Day 10 after CAR T (any FDA-approved CAR T product) infusion on Day 0.

autologous hematopoietic stem cells added to planned CAR T

Clinical Trial Recruitment Navigator

John Chute, MD

Justin Darrah, MD

Noah Merin, MD, PhD

Ronald Paquette, MD

Robert Vescio, MD

Hannah Lee, MD

Akil Merchant, MD

David Oveisi, MD

Leslie Ballas, MD

Joshua Sasine, MD, PhD

The study is designed to examine the feasibility and safety of collecting autologous hematopoietic stem cells (HSCs) to be combined with CAR T-cell therapy for patients with relapsed/refractory (r/r) hematological disease. The study will evaluate feasibility of collecting the target dose of HSCs from at least 50% of enrolled patients. The study will assess safety based on incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in the first 60 days post CAR T dosing, and also through the collection of adverse events (AEs) and serious adverse events (SAEs) as well as the durability of response after treatment with HSCs with CAR T. The study follows an open-label, single-center and single non-randomized cohort design. 20 subjects with r/r hematological malignancies will be enrolled and treated to evaluate the feasibility and preliminary safety of collecting autologous HSCs and combining them with CAR T-cell therapy.

Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies

IIT2022-04-Sasine-CAR-T: A Phase 1 Single-arm, Open-label Study to Evaluate the Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies

Target dose collection of autologous HSCs (2 to 5 x 106 CD34+ cells/kg) defined as collection from at least 50% of patients enrolled in this study by Day 10.

Safety will be assessed by incidence, severity, and duration of CRS per ASTCT consensus grading system. ASTCT CRS Consensus grading (Grade scale is 1-4) is based on 3 CRS parameters: fever, hypotension, and hypoxia. Higher grade indicates worse outcome.

Safety will be assessed by incidence, severity, and duration ICANS per ASTCT consensus grading system. ASTCT ICANS Consensus grading (Grade scale is 1-4) is based on 5 neurotoxicity domains: Immune Effector Cell-Associated Encephalopathy (ICE) score, level of consciousness, seizure, motor findings, raised intracranial pressure (ICP)/cerebral edema. Higher grade indicates worse outcome.

Response rate of CAR T will be defined as the proportion of subjects who experience partial response (PR) or complete response (CR) assessed at 6 weeks or day 60. Response criteria used will be according to type of disease: Response by International Myeloma Working Group (IMWG) Criteria (for multiple myeloma); Response by Center for International Blood and Marrow Transplant Research (CIMBTR) Criteria (for acute lymphoblastic leukemia); Response by Lugano Criterial (for lymphoma).

Recovery assessed by the proportion of patients with ANC recover to ≥ 500/µL.

The proportion of patients with RBC transfusion independence by Day 28.

The proportion of patients with platelet transfusion independence by Day 28.

Safety and tolerability will be assessed by the number of adverse events (AEs) and serious adverse events (SAEs) related to study treatment according to CTCAE v.5, up to Week 52.

PFS will be assessed from time of CAR T infusion until confirmation of disease progression or withdrawal of consent, whichever comes first.

OS will be assessed from date of CAR T infusion until date of death due to any cause or withdrawal of consent, whichever comes first.

Assistant Professor of Medicine, Co-Director, CAR T Program

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ralpha2 CAR (E-SYNC) T Cells	NCT06186401	EGFR Gene Mutat... Glioblastoma MGMT-Unmethylat... Recurrent Gliob...	E-SYNC T Cells Cyclophosphamid... Fludarabine (no... Leukapheresis Surgical resect...	18 Years -	University of California, San Francisco
Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies	NCT05887167	Hematologic Mal... Large B-cell Ly... Acute Lymphobla... Mantle Cell Lym... Multiple Myelom... Diffuse Large B...	autologous hema...	18 Years - 85 Years	Cedars-Sinai Medical Center
Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ralpha2 CAR (E-SYNC) T Cells	NCT06186401	EGFR Gene Mutat... Glioblastoma MGMT-Unmethylat... Recurrent Gliob...	E-SYNC T Cells Cyclophosphamid... Fludarabine (no... Leukapheresis Surgical resect...	18 Years -	University of California, San Francisco
Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies	NCT05887167	Hematologic Mal... Large B-cell Ly... Acute Lymphobla... Mantle Cell Lym... Multiple Myelom... Diffuse Large B...	autologous hema...	18 Years - 85 Years	Cedars-Sinai Medical Center

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