EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma

NCT02664363 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: Pro00069444
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Please note that enrollment on this study terminated early due to the end of grant funding. Newly diagnosed WHO grade IV malignant glioma subjects who are eligible were enrolled following surgery to remove their brain tumor. They then underwent a leukapheresis to harvest cells for the generation of the study drug, Epidermal Growth Factor variant III Chimeric Antigen Receptor (EGFRvIII CAR) T cells prior to beginning standard of care (SOC) radiation therapy (RT) with temozolomide (TMZ). Once SOC RT with TMZ was completed, subjects returned for the post-RT brain imaging assessment, and, if stable, started post-RT TMZ cycles. Patients received up to 3 cycles of dose-intensified TMZ prior to receiving the EGFRvIII CAR T cells, which was infused in dose escalation cohorts. Following a one-month delay between cycles, the subject resumed post-RT cycles of TMZ and were monitored with blood work and brain imaging as per SOC. An expanded cohort of 12 subjects was originally planned for once the maximally tolerated dose (MTD) was reached in the dose escalation cohorts, in order to obtain a more precise estimate of the probability of unacceptable toxicity and to track the EGFRvIII CAR T cells using 111 Indium (111In) labeling. Computed Tomography (CT) was planned on days 1, 2, and 3 post-infusion to determine intracerebral (IC) localization.

Conditions

Glioblastoma; Gliosarcoma

Outcome Measures

Primary Outcomes (1)

• Maximally Tolerated Dose

  Within this "3+3" phase I study, the primary objective is to determine the MTD of a single IV infusion of EGFRvIII CAR T cells in patients with newly-diagnosed WHO grade IV malignant glioma. Four dose levels were to be considered based on transduced cells/kg: #1: 4.5 x 10\^6/kg, #2: 1.5 x 10\^7/kg, #3: 4.5 x 10\^7/kg, and #4: 1.5 x 10\^8/kg. The MTD is the highest dose level at which ≤1 of 3-6 patients experience dose-limiting toxicity during the 4 weeks after CAR infusion.

  12-18 months

Secondary Outcomes (1)

• Number of Patients Who Experienced a Dose-limiting Toxicity (DLT)

  12-18 months

Study Arms (1)

EGFRvIII CAR T cells

EXPERIMENTAL

Dose escalation cohorts for 4 dose levels will be considered: #1: 4.5 x 10\^6/kg, #2: 1.5 x 10\^7/kg, #3: 4.5 x 10\^7/kg, and #4: 1.5 x 10\^8/kg. Starting at dose level 1, cohorts of 3-6 subjects will be accrued at each dose level.

Biological: EGFRvIII CAR T cells

Interventions

EGFRvIII CAR T cells BIOLOGICAL

The name of the drug is CAR gene-modified T cells or abbreviated as EGFRvIII CARs. The class of action is a biological and the mechanism of action is cytotoxicity. The drug substance is autologous T cells transduced with a retroviral vector encoding for a chimeric antigen receptor (CAR) directed against the tumor specific antigen, EGFRvIII. EGFRvIII CARs are genetically engineered T cells that have been taken from patients with GBM ex vivo to express a CAR recognizing the GBM tumor-specific antigen EGFRvIII, which is expressed on a subset of GBMs but not in normal human tissues with the aim of mediating regression of their tumors. Patients' CARs will be radiolabeled with 111In for correlative studies in the expanded cohort.

Also known as: EGFRvIII CARs, CAR-specific T cells, CAR T cells, CARs, 111Indium Labeled EGFRvIII CARs, 111In-Labeled EGFRvIII CARs, CAR gene-modified T cells, 111In-labeled CARs

EGFRvIII CAR T cells

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-80 years of age
• Histopathologically proven newly-diagnosed, supratentorial glioblastoma or gliosarcoma (World Health Organization \[WHO\] Grade IV)
• Karnofsky Performance Status (KPS) score ≥ 70
• The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR).
• Hematology:
• Absolute Neutrophil Count (ANC) ≥ 1000/mm\^3 without the support of filgrastim
• Platelet count ≥ 100,000/mm\^3
• Hemoglobin ≥ 8.0 g/dl (eligibility level for hemoglobin may be reached with transfusion)
• Chemistry:
• Alanine Amino Transferase (ALT)/Aspartate Amino Transferase (AST) ≤ 2.5 times the upper limit of normal
• Creatinine ≤ 1.6 mg/dl
• Total bilirubin ≤ 1.5 mg/dl

You may not qualify if:

• Patients who are pregnant, breast-feeding, or unwilling to practice an effective method of birth control
• Patients with known potentially anaphylactic allergic reactions to Gadolinium-Diethylene Triamine Pentaacetic Acid (gd-DTPA)
• Patients who cannot undergo Magnetic Resonance Imaging (MRI) or Single Photon Emission-Computed Tomography (SPECT) due to obesity or to having certain metal in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods, or plates)
• Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, or with evidence of leptomeningeal disease
• Active infection requiring treatment or an unexplained febrile (\> 101.5 F) illness
• Known autoimmune disease, immunosuppressive disease or human immunodeficiency virus (HIV) infection (i.e., known HIV or Hepatitis C)
• Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease
• Patients with previous history of radiosurgery, brachytherapy, gliadel implantation, or radiolabeled monoclonal antibodies
• Prior antitumor therapy for glioma (other than steroids)
• Allergic to TMZ

Sponsors & Collaborators

• Daniel Landi: lead

Study Sites (1)

The Preston Robert Tisch Brain Tumor Center at Duke

Durham, North Carolina, 27710, United States

Location

Related Publications (1)

• Suryadevara CM, Desai R, Abel ML, Riccione KA, Batich KA, Shen SH, Chongsathidkiet P, Gedeon PC, Elsamadicy AA, Snyder DJ, Herndon JE 2nd, Healy P, Archer GE, Choi BD, Fecci PE, Sampson JH, Sanchez-Perez L. Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology. 2018 Feb 21;7(6):e1434464. doi: 10.1080/2162402X.2018.1434464. eCollection 2018.

  PMID: 29872570 DERIVED

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma

Interventions

Immunotherapy, Adoptive; Automobiles

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)

Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Motor Vehicles; Transportation; Technology, Industry, and Agriculture

Results Point of Contact

• Title: Principal Investigator
• Organization: Duke University Medical Center

dukebrain1@duke.edu

9196845301

Study Officials

• David Ashley, MBBS, FRACP, PhD

  Duke University Hospital

  PRINCIPAL INVESTIGATOR

• Daniel Landi, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Pediatrics and Neurosurgery

Study Record Dates

• First Submitted: January 22, 2016
• First Posted: January 27, 2016
• Study Start: February 1, 2017
• Primary Completion: September 25, 2018
• Study Completion: September 12, 2019
• Last Updated: February 17, 2023
• Results First Posted: July 24, 2020

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)