Clinical Trials /

Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM

NCT03283631

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM
  • Official Title: INTERCEPT: INTracerebral EGFR-vIII Chimeric Antigen Receptor Gene-Modified T CElls for PaTients With Recurrent GBM

Clinical Trial IDs

  • ORG STUDY ID: Pro00083828
  • SECONDARY ID: 5P50CA190991-03
  • NCT ID: NCT03283631

Conditions

  • Recurrent Glioblastoma Multiforme
  • Recurrent Brain Tumor, Adult

Interventions

DrugSynonymsArms
EGFRvIII-CARsEGFRvIII-CARs

Purpose

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 multiforme (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.

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 -3 to -1,
      patients will have a BrainLab MRI to prepare for biopsy and catheter placement. On Day 0, 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 1 (+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, 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 108 of 111In-labeled cells in 3 milliliter (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.
    

Trial Arms

NameTypeDescriptionInterventions
EGFRvIII-CARsExperimentalGamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells

    Eligibility Criteria

            Inclusion Criteria:
    
              1. First disease progression or disease recurrence (≥ 1 cm and ≤ 5 cm) of a partially or
                 completely resectable, supratentorial WHO grade IV malignant glioma (GBM) based on
                 imaging studies with measurable disease.
    
              2. KPS score ≥ 70.
    
              3. EGFRvIII, the target antigen, must be identified on tumor tissue by IHC or PCR, i.e.
                 EGFRvIII positive via pathology report.
    
              4. Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/µl, platelets ≥ 125,000 cells/µl.
    
              5. Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of
                 normal
    
              6. Bevacizumab naïve.
    
              7. At least twelve weeks from completion of standard external beam radiation therapy and
                 temozolomide.
    
              8. Stable or decreasing steroid dose (≤ 4 mg/day) within 5 days prior to enrollment. If
                 patients are decreasing steroid use, once they get to 2 mg/day, they should be
                 supplemented with 10-20 mg of hydrocortisone.
    
              9. Signed informed consent approved by the Institutional Review Board.
    
             10. 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 first study treatment.
    
             11. 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.
    
             12. 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
                 sterotactic 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 multifocal disease, or leptomeningeal disease.
    
              5. 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.
    
              6. Co-medication that may interfere with study results; e.g. immuno-suppressive agents
                 other than corticosteroids.
    
              7. 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;
    
              8. Current, recent (within 4 weeks of the administration of this study agent), or planned
                 participation in another experimental therapeutic drug study.
    
              9. Patients with an active infection requiring treatment or having an unexplained febrile
                 illness (Tmax > 99.5 F).
    
             10. Prior therapy targeted to EGFRvIII.
    
             11. Prior history of brain SRS, (patients who have received external beam radiation per
                 standard of care are allowed).
          
    Maximum Eligible Age:80 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Determination of Maximum Tolerated Dose (MTD)
    Time Frame:4 weeks
    Safety Issue:
    Description:MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM

    Secondary Outcome Measures

    Measure:Assessment of T Cell trafficking within the brain
    Time Frame:2 days
    Safety Issue:
    Description:Change in volume of distribution and maximal percentage of enhanced tumor volume covered
    Measure:Median survival
    Time Frame:1 year
    Safety Issue:
    Description:The time between SRS / CAR treatment and death or last follow-up
    Measure:Median progression-free survival
    Time Frame:1 year
    Safety Issue:
    Description:The time between SRS / CAR treatment and first failure (death or disease progression)

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Gary Archer Ph.D.

    Trial Keywords

    • Malignant Glioma
    • INTERCEPT
    • Pro00083828
    • Desjardins
    • Adult
    • Chimeric Antigen Receptor
    • CAR T cell

    Last Updated

    September 13, 2017