Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM

NCT03283631 | Terminated Phase 1 FDA Drug

• 2 other identifiers: Pro000838285P50CA190991-03
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this protocol is to transfer autologous peripheral blood mononuclear cells (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are genetically engineered with a viral vector encoding the CAR and infused directly into the patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being targeted to a tumor specific antigen, given the prior toxicity using CARs that were not targeted to tumor-specific antigens, the investigators elected to begin with very low doses of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce the anticipated number of participants was under review and approved. The decision to terminate the study was made in January, 2021 to shift toward the next iteration of a related CAR T cell trial.

Conditions

Recurrent Glioblastoma; Recurrent Gliosarcoma

Keywords

Malignant Glioma; INTERCEPT; Pro00083828; Adult; Chimeric Antigen Receptor; CAR T cell; EGFRvIII

Outcome Measures

Primary Outcomes (1)

• Determination of Maximum Tolerated Dose (MTD)

  MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM

  4 weeks

Secondary Outcomes (4)

• Assessment of T Cell trafficking within the brain tumor

  2 days

• Assessment of T cell trafficking systemically

  2 days

• Median survival

  1 year

• Median progression-free survival

  1 year

Study Arms (1)

EGFRvIII-CARs

EXPERIMENTAL

Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells

Biological: EGFRvIII-CARs

Interventions

EGFRvIII-CARs BIOLOGICAL

Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells

EGFRvIII-CARs

Eligibility Criteria

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

You may qualify if:

• Disease progression or recurrence of a supratentorial World Health Organization (WHO) grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease. At the time of biopsy, prior to stereotactic radiosurgery (SRS) and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be confirmed by histopathological analysis.
• Adults ≥ 18 years old.
• Karnofsky Performance Status (KPS) score ≥ 70.
• EGFRvIII, the target antigen, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR), i.e. EGFRvIII positive via pathology report.
• Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥ 125,000 cells/µl (prior to biopsy).
• Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT), and bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).
• Signed informed consent approved by the Institutional Review Board.
• Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, \[i.e. with a failure rate of \< 1% per year\] are implants, injectables, combined oral contraceptives, intra-uterine device \[IUD; only hormonal\], sexual abstinence or vasectomized partner) during the trial and for a period of \> 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 48 hours prior to starting SRS.
• Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control \[i.e. with a failure rate of \< 1% per year\] include a female partner using implants, injectables, combined oral contraceptives, IUDs \[only hormonal\], sexual abstinence or prior vasectomy) during the trial and for a period of \> 6 months following the last administration of trial drugs.
• Meet eligibility requirements for SRS: able to get MRI; the patient must have a lesion that, in the opinion of the study radiation oncologist, can safely receive SRS to the entire tumor; must not be abutting optic apparatus or brainstem and catheter tip will be at least 5mm away from the ventricle; and must be able to be secured and positioned in a stereotactic U-frame mask.

You may not qualify if:

• Pregnant or breast-feeding.
• Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.
• Patients who cannot undergo MRI with contrast or SPECT/CT.
• Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or spinal cord, radiological evidence of actively growing multifocal disease, or leptomeningeal disease.
• Patients \< 12 weeks from the end of radiation therapy, unless they have two progressive scans at least 4 weeks apart, have progression outside of the radiation field, or have histologic confirmation of progression.
• Severe, active comorbidity, including any of the following:
• Unstable angina and/or congestive heart failure requiring hospitalization;
• Transmural myocardial infarction within the last 6 months;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study initiation;
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy;
• Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
• Known autoimmune disorder, such as HIV;
• Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy;
• Active connective tissue disorders, such as lupus or scleroderma that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity.
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.

Sponsors & Collaborators

• Gary Archer Ph.D.: lead
• National Cancer Institute (NCI): collaborator
• Duke Cancer Institute: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Links

• The Preston Robert Tisch Brain Tumor Center
• Duke Cancer Institute

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Glioma

Condition Hierarchy (Ancestors)

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

Study Officials

• Daniel Landi, MD

  Duke University

  PRINCIPAL INVESTIGATOR

• David Ashley, MBBS, FRACP, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

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 Neurosurgery

Study Record Dates

• First Submitted: September 13, 2017
• First Posted: September 14, 2017
• Study Start: May 30, 2018
• Primary Completion: September 19, 2019
• Study Completion: June 30, 2020
• Last Updated: April 5, 2021

Record last verified: 2021-04

Locations

US (1)