Clinical Trials /

CART-EGFRvIII + Pembrolizumab in GBM

NCT03726515

Description:

This is an open-label, phase 1 study to assess the safety and tolerability of EGFRvIII T cells in combination with pembrolizumab (PD-1 Inhibitor) in patients with newly diagnosed, EGFRvIII+, MGMT-unmethylated glioblastoma.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CART-EGFRvIII + Pembrolizumab in GBM
  • Official Title: Phase 1 Study of EGFRvIII-Directed CAR T Cells Combined With PD-1 Inhibition in Patients With Newly Diagnosed, MGMT-Unmethylated Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 831706, UPCC 13318
  • NCT ID: NCT03726515

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
CART-EGFRvIII T cellsCART-EGFRvIII + Pembrolizumab
PembrolizumabKeytrudaCART-EGFRvIII + Pembrolizumab

Purpose

This is an open-label, phase 1 study to assess the safety and tolerability of EGFRvIII T cells in combination with pembrolizumab (PD-1 Inhibitor) in patients with newly diagnosed, EGFRvIII+, MGMT-unmethylated glioblastoma.

Trial Arms

NameTypeDescriptionInterventions
CART-EGFRvIII + PembrolizumabExperimental

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Newly diagnosed glioblastoma (GBM) that is histologically confirmed by pathology
                 review of surgically resected tissue.
    
              2. Undergone either a gross total resection or near total resection.
    
              3. No prior systemic therapies, radiation, tumor-treating fields, or intratumoral
                 therapeutic agents including Gliadel wafers are allowed. Gross or near total resection
                 must be the only tumor-directed treatment that the patient has received for
                 glioboblastoma.
    
              4. Tumor tissue tests positive for EGFRvIII expression, as performed by the University of
                 Pennsylvania's in-house fusion transcript panel (RNA-based assay using Illumina HiSeq
                 platform). Outside EGFRvIII expression testing is not allowed.
    
              5. Tumor tissue tests negative for MGMT promoter methylation (i.e. the tumor is
                 MGMT-unmethylated), as performed by the University of Pennsylvania's in-house
                 pyrosequencing protocol. Outside MGMT testing is not allowed.
    
              6. Patients ≥ 18 years of age
    
              7. ECOG performance status 0-1
    
              8. Provides written informed consent
    
              9. Must have adequate organ function as measured by:
    
                   1. White blood count ≥ 2500/mm3; platelets ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL;
                      without transfusion or growth factor support
    
                   2. AST, ALT, GGT, LDH, alkaline phosphatase within 2.5 x upper normal limit, and
                      total bilirubin ≤ 2.0 mg/dL
    
                   3. Serum creatinine < 1.5 x upper limit of normal
    
                   4. Adequate cardiac function (LVEF ≥ 45%)
    
             10. Subjects of reproductive potential must agree to use acceptable birth control methods.
    
            Exclusion Criteria:
    
              1. Pregnant or lactating women
    
              2. Inadequate venous access for or contraindications to leukapheresis.
    
              3. Active Hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled
                 infection
    
              4. History of allergy or hypersensitivity to study product excipients (human serum
                 albumin, DMSO, and Dextran 40)
    
              5. History of severe hypersensitivity reactions to other monoclonal antibodies which in
                 the opinion of the investigator may post an increased risk of serious infusion
                 reactions.
    
              6. Requirement for immunosuppressive agents including but not limited to cyclosporine,
                 MMF, tacrolimus, rapamycin, or anti-TNF agents within 4 weeks of eligibility
                 confirmation by the physician-investigator.
    
              7. Subjects with a history of known or suspected, severe or uncontrolled autoimmune or
                 connective tissue disease. Patients with vitiligo, controlled type 1 diabetes mellitus
                 (on stable insulin dose), residual autoimmune-related hypothyroidism (due to
                 autoimmune condition only requiring hormone replacement), or psoriasis (not requiring
                 systemic treatment), or conditions not expected to recur in the absence of an external
                 trigger, are permitted to enroll.
    
              8. Known history or current interstitial lung disease or non-infectious pneumonitis
    
              9. Prior allogenic bone marrow or solid organ transplant
    
             10. Any concurrent malignancy other than non-melanoma skin cancer that has been curatively
                 treated, or carcinoma in situ of the cervix or bladder that has been curatively
                 treated. For any prior invasive malignancy, at least 5 years must have elapsed since
                 curative therapy and patients must not have received any radiation to the brain.
                 Monoclonal gammopathy of undetermined significance (MGUS) is permitted.
    
             11. Any uncontrolled active medical or psychiatric disorder that would preclude
                 participation as outlined.
    
             12. Severe, active co-morbidity in the opinion of the physician-investigator would
                 preclude participation in this study, including but not limited to the following:
    
                   1. Unstable angina within 6 months prior to eligibility confirmation by the
                      physician-investigator
    
                   2. Transmural myocardial infarction within the last 6 months prior to eligibility
                      confirmation by the physician-investigator
    
                   3. New York Heart Association grade II or greater congestive heart failure requiring
                      hospitalization within 12 months prior to eligibility confirmation by the
                      physician-investigator.
    
                   4. Serious and inadequately controlled cardiac arrhythmia
    
                   5. Serious or non-healing wound, ulcer, or history of abdominal fistula,
                      gastrointestinal perforation, intra-abdominal abscess major surgical procedure,
                      open biopsy, or significant traumatic injury within 28 days prior to eligibility
                      confirmation by the physician-investigator, with the exception of the craniotomy
                      for tumor resection.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of subjects with treatment-related adverse events, using NCI CTCAE v5.0.
    Time Frame:5 Months
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:Overall survival Rate
    Time Frame:15 Years
    Safety Issue:
    Description:Number of days from the date of the first CART-EGFRvIII infusion to the date of death of any cause. The survival function of OS will be calculated by the Kaplan-Meier method.
    Measure:Progression-free survival (PFS)
    Time Frame:15 Years
    Safety Issue:
    Description:The number of days from the date of the first CART-EGFRvIII infusion to the first documented disease progression (based on standard MRI evaluation using the modified RANO criteria) or date of death, whichever occurs first. PFS will be calculated by the Kaplan-Meier method.
    Measure:Objective response rate (ORR)
    Time Frame:15 Years
    Safety Issue:
    Description:The proportion of patients with complete response (CR) or partial response (PR) out of the total number of efficacy evaluable subjects. Exact 90%confidence interval for ORR will be computed.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:University of Pennsylvania

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