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

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ClinicalTrials.gov Identifier: NCT03283631
Recruitment Status : Recruiting
First Posted : September 14, 2017
Last Update Posted : October 16, 2018
Sponsor:
Collaborators:
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 prior to any other intervention to treat recurrence. 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.


Study Type : Interventional
Estimated Enrollment : 24 participants
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

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

Inclusion Criteria:

  1. First disease progression or disease recurrence (≥ 1 cm and ≤ 5 cm) of a supratentorial WHO grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease. At the time of biopsy, prior to SRS and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be confirmed by histopathological analysis.
  2. Adults ≥ 18 years old.
  3. KPS score ≥ 70.
  4. EGFRvIII, the target antigen, must be identified on tumor tissue by IHC or PCR, i.e. EGFRvIII positive via pathology report.
  5. Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/µl, platelets ≥ 125,000 cells/µl (prior to biopsy).
  6. Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).
  7. Bevacizumab naïve.
  8. Signed informed consent approved by the Institutional Review Board.
  9. 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.
  10. 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.
  11. Meet eligibility requirements for SRS: able to get MRI, lesion must not be abutting optic apparatus or brainstem, 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 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 with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5 F, 37.5 C).
  11. Prior therapy targeted to EGFRvIII.
  12. 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 ClinicalTrials.gov identifier (NCT number): NCT03283631


Contacts
Contact: Stevie Threatt 919-684-5301 dukebrain1@duke.edu
Contact: Susan Boulton, RN, BSN 919-684-5301 dukebrain1@duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Stevie Threatt    919-684-5301    dukebrain1@duke.edu   
Contact: Susan Boulton, RN, BSN    919-684-5301    dukebrain1@duke.edu   
Sponsors and Collaborators
Gary Archer Ph.D.
National Cancer Institute (NCI)
Duke Cancer Institute
Investigators
Principal Investigator: Daniel Landi, MD Duke University
Principal Investigator: David Ashley, MBBS, FRACP, PhD Duke University

Additional Information:
Responsible Party: Gary Archer Ph.D., Assistant Professor of Neurosurgery, Duke University
ClinicalTrials.gov Identifier: NCT03283631     History of Changes
Other Study ID Numbers: Pro00083828
5P50CA190991-03 ( U.S. NIH Grant/Contract )
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018

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
INTERCEPT
Pro00083828
Adult
Chimeric Antigen Receptor
CAR T cell
EGFRvIII

Additional relevant MeSH terms:
Glioma
Glioblastoma
Gliosarcoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue