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Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM (INTERCEPT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03283631
Recruitment Status : Suspended (We are temporally halting enrollment until a protocol amendment is approved.)
First Posted : September 14, 2017
Last Update Posted : April 22, 2020
National Cancer Institute (NCI)
Duke Cancer Institute
Information provided by (Responsible Party):
Gary Archer Ph.D., Duke University

Brief Summary:
Malignant primary brain tumors account for more human deaths than melanoma or cancer of the bladder or kidney. The non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissue. Thus, in order to reduce off-site effects and be more effective, therapeutic strategies will have to target tumor cells precisely while minimizing collateral damage to the neighboring cerebral cortex. 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 will be 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 will be 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 have elected to begin with very low doses of cells.

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Recurrent Gliosarcoma Biological: EGFRvIII-CARs Phase 1

Detailed Description:

Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original tumor diagnosis will have autologous PBMCs harvested by leukapheresis. These autologous PBMCs will be transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of leukapheresis, on Day -4 to -2, patients will have a BrainLab MRI to prepare for biopsy and catheter placement. On Day -1, the patient will undergo standard of care (SOC) stereotactic biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to catheter insertion and administration of study drug, the presence of recurrent tumor must be confirmed by histopathology. If tumor recurrence is confirmed, a catheter will be placed intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).

After biopsy, on the same day, a planning MRI will be performed in the Department of Radiation Oncology for SRS planning and a CT scan will be done for SRS masking. SRS will take place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs will be infused on the same day over a 6 to 6.5 hour period immediately after SRS.

On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging will assess the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that describes the distribution of EGFRvIII-CARs within the brain and systemically.

This protocol is designed to determine the maximum tolerated dose (MTD) of a novel, tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose will be 2.5 x 10^8 of 111In-labeled cells in 3 milliliters (mL). Doses will be escalated in successive cohorts. The infusion flow rate will be fixed at 0.5 mL/hr. Infusions of this volume and flow rate have been previously used by us for other therapeutics and have been shown to be safe. EGFRvIII-CARs dose escalation will be accomplished by increasing cell concentration allowing flow rate and infusion volume to remain unchanged. Cell dose will be increased in successive cohorts so long as dose-limiting toxicities (DLTs) are not observed as described below.

In the rare event that a sufficient amount of CAR-specific T cells cannot be generated for a patient's intended dose within the dose-escalation portion of this study, the patient will be treated with all cells if within 15% of the intended dose. If the cell number is not within 15% of the intended dose, the patient will be treated at a lower pre-defined dose level using available CAR-specific T cells. If the situation of an insufficient number of CAR-specific T cells occurs within the expanded cohort, all available cells will be administered. If the number of CAR-specific T cells is not within 15% of the intended dose, an additional patient will be treated in the expanded cohort.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: INTERCEPT: INTracerebral EGFR-vIII Chimeric Antigen Receptor Gene-Modified T CElls for PaTients With Recurrent GBM
Actual Study Start Date : May 30, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: EGFRvIII-CARs
Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells
Biological: EGFRvIII-CARs
Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells

Primary Outcome Measures :
  1. Determination of Maximum Tolerated Dose (MTD) [ Time Frame: 4 weeks ]
    MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM

Secondary Outcome Measures :
  1. Assessment of T Cell trafficking within the brain tumor [ Time Frame: 2 days ]
    Change in volume of distribution and maximal percentage of enhanced tumor volume covered

  2. Assessment of T cell trafficking systemically [ Time Frame: 2 days ]
    Change in the volume of distribution of 111In-labeled EGFRvIII-CARs present in each body area (neck, chest, abdomen, pelvis, and extremities)

  3. Median survival [ Time Frame: 1 year ]
    The time between SRS / CAR treatment and death or last follow-up

  4. Median progression-free survival [ Time Frame: 1 year ]
    The time between SRS / CAR treatment and first failure (death or disease progression)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 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.
  2. Adults ≥ 18 years old.
  3. Karnofsky Performance Status (KPS) score ≥ 70.
  4. 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.
  5. Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥ 125,000 cells/µl (prior to biopsy).
  6. Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT), and bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).
  7. Signed informed consent approved by the Institutional Review Board.
  8. 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.
  9. 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.
  10. 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.

Exclusion Criteria:

  1. Pregnant or breast-feeding.
  2. Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.
  3. Patients who cannot undergo MRI with contrast or SPECT/CT.
  4. Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or spinal cord, radiological evidence of actively growing multifocal disease, or leptomeningeal disease.
  5. 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.
  6. Severe, active comorbidity, including any of the following:

    1. Unstable angina and/or congestive heart failure requiring hospitalization;
    2. Transmural myocardial infarction within the last 6 months;
    3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study initiation;
    4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy;
    5. Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
    6. Known autoimmune disorder, such as HIV;
    7. Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy;
    8. 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.
  7. Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.
  8. Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin;
  9. Current, recent (within 4 weeks of the administration of this study agent), or planned participation in another experimental therapeutic drug study.
  10. Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)] prior to biopsy unless patients have recovered from side effects of such therapy.
  11. Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5 F, 37.5 C).
  12. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to CAR T Cell infusion.
  13. Prior therapy targeted to EGFRvIII.
  14. Prior history of brain SRS, (patients who have received external beam radiation per standard of care are allowed).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03283631

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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Gary Archer Ph.D.
National Cancer Institute (NCI)
Duke Cancer Institute
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Principal Investigator: Daniel Landi, MD Duke University
Principal Investigator: David Ashley, MBBS, FRACP, PhD Duke University
Additional Information:
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Responsible Party: Gary Archer Ph.D., Assistant Professor of Neurosurgery, Duke University Identifier: NCT03283631    
Other Study ID Numbers: Pro00083828
5P50CA190991-03 ( U.S. NIH Grant/Contract )
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: April 22, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gary Archer Ph.D., Duke University:
Malignant Glioma
Chimeric Antigen Receptor
CAR T cell
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue