Clinical Trials /

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

NCT02664363

Description:

Newly diagnosed WHO grade IV malignant glioma subjects who are eligible will be enrolled following surgery to remove the brain tumor. They will then undergo 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 is completed, subjects will return for the post-RT brain imaging assessment, and if stable will start post-RT TMZ cycles. Patients will receive up to 3 cycles of dose intensified TMZ prior to receiving the EGFRvIII CAR T cells, which will be infused in dose escalation cohorts. Following a one month delay between cycles, the subject will resume post-RT cycles of TMZ and be monitored with blood work and brain imaging as per SOC. Once the maximally tolerated dose (MTD) is reached in the dose escalation cohorts, an expanded cohort of 12 subjects will be enrolled 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) will be done on days 1, 2, and 3 post-infusion to determine intracerebral (IC) localization.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: EGFRvIII CAR T Cells for Newly-Diagnosed GBM
  • Official Title: EGFRvIII Chimeric Antigen Receptor (CAR) Gene-modified T Cells for Patients With Newly-Diagnosed GBM During Lymphopenia

Clinical Trial IDs

  • ORG STUDY ID: Pro00069444
  • NCT ID: NCT02664363

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms

Purpose

Newly diagnosed glioblastoma subjects who are eligible will be enrolled following surgery to remove the brain tumor. They will then undergo 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 is completed, subjects will return for the post-RT brain imaging assessment, and if stable will start post-RT TMZ cycles. During the 3rd cycle of post-RT TMZ, the EGFRvIII CAR T cells will be infused in dose escalation cohorts. Following a one month delay between cycles, the subject will resume post-RT cycles of TMZ and be monitored with blood work and brain imaging as per SOC. Once the maximally tolerated dose (MTD) is reached in the dose escalation cohorts, an expanded cohort of 12 subjects will be enrolled 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) will be done on days 1, 5, and 10 post-infusion to determine intracerebral (IC) localization.

Detailed Description

Following consent, subjects will be enrolled onto dose-escalation cohorts. Patients will undergo leukapheresis to harvest Peripheral Blood Mononuclear Cells (PBMCs) for the generation of EGFRvIII CAR T cells prior to beginning RT and concurrent TMZ. T cells will be isolated from the patient's PBMCs and transduced to express S. Briefly, PBMC will be stimulated with Muromonab-cluster of differentiation 3 (CD3) (OKT3), an anti-CD3 monoclonal antibody (mAb) and transduced on RetroNectin® coated plates. Transduced cells will be expanded in interleukin-2 (IL-2) for 14 days.

Patients will then complete 6 weeks of standard of care RT and concurrent TMZ at a targeted dose of 75 mg/m^2/d. Patients who experience progressive disease during radiation, who are unable to tolerate TMZ, or who require TMZ dose modification will be withdrawn from the study and replaced.

The remaining patients will then receive the initial cycle of TMZ at 50-100 mg/m^2/day for 21 days, followed by 2 more cycles of 100 mg/m^2/day for 21 days every 28 days, which is the standard dose-intensified (DI) TMZ regimen. If the patient is unable to tolerate DI TMZ or the CAR-specific T cells do not meet release criteria, the patient will be withdrawn before CAR treatment and replaced.

On day 22 (+3 day window) of the third post-radiation cycle of DI TMZ, the total dose of EGFRvIII CAR T cells will be delivered intravenously. If sufficient CAR-specific T cells cannot be generated to meet the targeted assigned dose within the dose-escalation portion of the study, the patient will be treated at a lower pre-defined dose level using available CAR-specific T cells and replaced in the assigned higher dose. The administered dose will be the highest defined dose level for which there are sufficient CAR-specific T cells available. Within the expanded cohort, if sufficient CAR-specific T cells can't be generated to meet the MTD dose, all available T cells will be administered.

Following the infusion of EGFRvIII CARs, blood samples for immune monitoring will be drawn 1, 5, and 10 days after the infusion, then 1, 3, and 6 months, then yearly until progression (or death or lost to contact). The return visits for immune monitoring at the 3, 6, and yearly will coincide with standard of care clinic visits. Blood will also be taken for Replication Competent Retrovirus (RCR) Polymerase Chain Reaction (PCR) per the Food and Drug Administration (FDA) at 3, 6 and 12 months during standard of care clinic visits. Lastly, blood for evaluation of cytokine release syndrome (CRS) will be drawn prior to cell infusion, 1 and 4 hours after infusion, and on days 1, 2, 5, 10, and at one month. Measurements for CRS include IL-2, IL-6, Tumor Necrosis Factor alpha (TNFα), interferon (IFN) gamma, Granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein (CRP).

Patients will return to clinic one month following the EGFRvIII CAR T cell infusion to be evaluated for cycles of standard of care 5-day TMZ at 150-200 mg/m^2/day for the first 5-day cycle, followed by 200 mg/m^2/day for 5-days every 28 days per the treating oncologist. This will result in a 28-day delay between TMZ cycles 3 and 4 in order to decrease the chance of study drug washout from TMZ.

Tumor progression will be documented histologically, unless there are clinical contraindications, to exclude inflammatory responses presenting as radiographic or clinical changes, which could indicate a potentially toxic or therapeutic responses and not tumor progression. If tissue is obtained through Tissue Bank Consent Institutional Review Board (IRB) # 2635, it will be used to confirm tumor progression histologically, and to assess immunologic cell infiltration and EGFRvIII antigen escape at the tumor site. Patients will be eligible for additional adjuvant therapy at the time of tumor progression.

A classical "3+3" study design will be used to estimate the MTD for CAR-specific T cells treatment among patients with newly-diagnosed GBM. Four 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 with the lowest dose level, cohorts of 3-6 subjects will be accrued at each dose level. If a patient is lost to follow-up during the first 4 weeks after CAR treatment without experiencing a dose-limiting toxicity (DLT), then the patient will not be evaluable for the determination of DLT and will be replaced. The MTD is the highest dose level at which ≤1 of 6 patients experiences DLT during the 4 week observation period after CAR treatment.

An expanded cohort of a total of 12 patients will be enrolled at the MTD of EGFRvIII CAR T cells in order to obtain a more precise estimate of the probability of unacceptable toxicity. This cohort will also have the cells radiolabeled with 111In to track their distribution. Briefly, CARs will be counted and re-suspended in phosphate buffered saline (PBS). 4-6x10^8 cells will be labeled with 500 microCi of 111In. The cells will be washed and mixed with cold CARs to achieve the desired cell dose. The labeled CARs will be infused into the patient through an intravenous catheter within the Ambulatory Bone Marrow Transplant (BMT) Unit. Distribution of 111In-labeled EGFRvIII CARs will be evaluated at 1, 5 and 10 days post-infusion using scintigraphy.

Trial Arms

NameTypeDescriptionInterventions
EGFRvIII CAR T cellsExperimentalDose 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.

    Eligibility Criteria

    Inclusion Criteria:

    1. Age 18-80 years of age

    2. Histopathologically proven newly-diagnosed, supratentorial malignant primary brain tumor (World Health Organization (WHO) Grade IV GBM) who have undergone surgical biopsy or excision with residual disease (>2cm).

    3. Karnofsky Performance Status (KPS) score ≥ 70.

    4. The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR).

    5. Stable or decreasing steroid dose within 5 days prior to enrollment.

    6. Hematology:

    - White Blood Count (WBC) ≥ 3000/mm^3

    - Absolute Neutrophil Count (ANC) ≥ 1000/mm^3 without the support of filgrastim

    - Platelet count ≥ 100,000/mm^3

    - Hemoglobin ≥ 8.0 g/dl

    7. 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.

    Exclusion Criteria:

    1. Patients who are pregnant, breast-feeding, or unwilling to practice an effective method of birth control.

    2. Patients with known potentially anaphylactic allergic reactions to Gadolinium-Diethylene Triamine Pentaacetic Acid (gd-DTPA).

    3. 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).

    4. Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, radiological evidence of multifocal disease, or leptomeningeal disease.

    5. Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness.

    6. Known autoimmune disease, immunosuppressive disease or human immunodeficiency virus (HIV) infection (i.e., known HIV or Hepatitis C).

    7. Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease.

    8. Patients with previous history of radiosurgery, brachytherapy, gliadel implantation, or radiolabeled monoclonal antibodies.

    9. Prior antitumor therapy for glioma (other than steroids).

    Maximum Eligible Age:80 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:MTD
    Time Frame:12-18 months
    Safety Issue:
    Description:The primary objective is to determine the MTD of a single IV infusion of EGFRvIII CAR T cells in patients with newly-diagnosed GBM.

    Secondary Outcome Measures

    Measure:DLT
    Time Frame:12-18 months
    Safety Issue:
    Description:To determine the DLT of a single IV infusion EGFRvIII CAR T cells in patients with newly-diagnosed GBM.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Gary Archer Ph.D.

    Trial Keywords

      Last Updated

      February 6, 2017