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Pilot Study of Autologous Anti-EGFRvIII CAR T Cells in Recurrent Glioblastoma Multiforme

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.
 
ClinicalTrials.gov Identifier: NCT02844062
Recruitment Status : Unknown
Verified July 2016 by Beijing Sanbo Brain Hospital.
Recruitment status was:  Recruiting
First Posted : July 26, 2016
Last Update Posted : July 26, 2016
Sponsor:
Collaborator:
Marino Biotechnology Co., Ltd.
Information provided by (Responsible Party):
Beijing Sanbo Brain Hospital

Study Description
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Brief Summary:
Chimeric antigen receptor (CAR)-modified T cells can mediate long-term durable remissions in recurrent or refractory CD19+ B cell malignancies, and are a promising therapy to treat glioblastoma, which is the most dangerous and aggressive form of brain cancer. EGFRvIII mutation (epidermal growth factor receptor variant III, EGFRvIII) is the results of tumor specific gene rearrangement naturally happened in about 30% of glioblastoma patients and produces a mutated protein with neo-antigen that is tumor specific and is not expressed in normal human tissues. Therefore, EGFRvIII is an attractive target for CAR T cell therapy. We have constructed a lentiviral vector that contains a chimeric antigen receptor that recognizes the EGFRvIII tumor antigen. A truncated EGFR (tEGFR) which lacks of the ligand binding domain and cytoplasmic kinase domain of wildtype EGFR is incorporated into the CAR vector and is used for in vivo tracking and ablation of CAR T cells in necessary. This pilot study is to determine the safety and efficacy of autologous anti-EGFRvIII CAR T cells in patients with recurrent glioblastoma.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Biological: anti-EGFRvIII CAR T cells Drug: cyclophosphamide Drug: Fludarabine Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Safety and Efficacy Study of Autologous Chimeric Antigen Receptor Engineered T Cells Redirected to EGFRvIII in Patients With Recurrent Glioblastoma Multiforme
Study Start Date : July 2016
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: anti-EGFRvIII CAR T cells
Patients will receive lymphodepletion chemotherapy consisting of fludarabine and cyclophosphamide, followed by intravenous infusion of autologous anti-EGFRvIII CAR T cells. A standard 3+3 escalation approach will be used to obtain the safe dosage of CAR T cells. The tested CAR T cell dosage ranges from 5×10^4 /kg to 1×10^7 /kg
 Biological: anti-EGFRvIII CAR T cells
CAR T cells are infused intravenously to patients in a three-day split-dose regimen（day0,10%; day1, 30%; day2, 60%）with a total targeted dose.

Drug: cyclophosphamide
250 mg/m^2 d1-3

Drug: Fludarabine
25mg/m^2 d1-3


Outcome Measures
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Primary Outcome Measures :
  1. Safety of infusion of autologous anti-EGFRvIII CAR T cells with cyclophosphamide and fludarabine as lymphodepleting chemotherapy in patients with recurrent glioblastoma using the NCI CTCAE V4.0 criteria. [ Time Frame: 2 years ]
    incidents of treatment related adverse events as assessed by CTCAE V4.0.


Secondary Outcome Measures :
  1. Treatment Responses Rate [ Time Frame: 4 weeks ]
    defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).

  2. Overall Survival Rate [ Time Frame: 2 years ]
  3. Progression-free Survival Rate [ Time Frame: 2 years ]
  4. Persistence of CAR T cells in patients [ Time Frame: 2 years ]

Other Outcome Measures:
  1. Proliferation of CAR T cells in patients [ Time Frame: 2 years ]
    CAR T cell proliferation in patients is monitored by flow or qPCR


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. abilities to understand and the willingness to provide written informed consent;
  2. patients are ≥ 18 and ≤ 70 years old;
  3. recurrent glioblastoma patients with measurable tumors. Patients have received standard care of medication, such as Gross Total Resection with concurrent Radio-chemotherapy (~54 - 60 Gy, TMZ). Patients must either not be receiving dexamethasone or receiving ≤ 4 mg/day at the time of leukopheresis;
  4. Malignant cells are EGFRvIII positive confirmed by IHC, quantitative PCR or sequencing;
  5. karnofsky performance score (KPS) ≥ 60;
  6. life expectancy >3 months;
  7. satisfactory bone marrow, liver and kidney functions as defined by the following: absolute neutrophile count ≥ 1500/mm^3; hemoglobin > 10 g/dL; platelets > 100000 /mm^3; Bilirubin < 1.5×ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5×ULN; creatinine < 1.5×ULN;
  8. peripheral blood absolute lymphocyte count must be above 0.8×10^9/L;
  9. satisfactory heart functions;
  10. patients must be willing to follow the orders of doctors;
  11. women of reproductive potential (between 15 and 49 years old) must have a negative pregnancy test within 7 days of study start. Male and female patients of reproductive potential must agree to use birth control during the study and 3 months post study.

Exclusion Criteria:

  1. a prior history of gliadel implantation 4 weeks before this study start or antibody based therapies;
  2. HIV positive;
  3. hepatitis B infection or hepatitis C infection;
  4. history of autoimmune disease, or other diseases require long-term administration of steroids or immunosuppressive therapies;
  5. history of allergic disease, or allergy to CAR T cells or study product excipients;
  6. patients already enrolled in other clinical study;
  7. patients, in the opinion of investigators, may not be eligible or not able to comply with the study.
Contacts and Locations
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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): NCT02844062


Contacts
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Contact: Zhixiong Lin, MD +86-10-13905918963 lzx1967@sina.com

Locations
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China
Sanbo Brain Hospital Capital Medical University Recruiting
Beijing, China, 100093
Contact: Zhixiong Lin, MD    +86-10-13905918963    lzx1967@sina.com   
Sponsors and Collaborators
Beijing Sanbo Brain Hospital
Marino Biotechnology Co., Ltd.
Investigators
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Principal Investigator: Zhixiong Lin, MD Capital Medical University
More Information
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Responsible Party: Beijing Sanbo Brain Hospital
ClinicalTrials.gov Identifier: NCT02844062    
Other Study ID Numbers: SBNK-2016-015-01
First Posted: July 26, 2016    Key Record Dates
Last Update Posted: July 26, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
 Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists