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

A Safety and Efficacy Study of Autologous Chimeric Antigen Receptor Engineered T Cells Redirected to EGFRvIII in Patients With Recurrent Glioblastoma Multiforme

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.

Study Overview

• Status: Unknown
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Biological: anti-EGFRvIII CAR T cells; Drug: cyclophosphamide; Drug: Fludarabine

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100093
    • Recruiting
    • Sanbo Brain Hospital Capital Medical University
    • Contact: Zhixiong Lin, MD; Phone Number: +86-10-13905918963; Email: lzx1967@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	incidents of treatment related adverse events as assessed by CTCAE V4.0.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival Rate		2 years
Treatment Responses Rate	defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).	4 weeks
Progression-free Survival Rate		2 years
Persistence of CAR T cells in patients		2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proliferation of CAR T cells in patients	CAR T cell proliferation in patients is monitored by flow or qPCR	2 years

Collaborators and Investigators

• Sponsor: Beijing Sanbo Brain Hospital
• Collaborators: Marino Biotechnology Co., Ltd.
• Investigators: Principal Investigator: Zhixiong Lin, MD, Capital Medical University

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Anticipated): July 1, 2018
• Study Completion (Anticipated): July 1, 2019

Study Registration Dates

• First Submitted: July 22, 2016
• First Submitted That Met QC Criteria: July 22, 2016
• First Posted (Estimate): July 26, 2016

Study Record Updates

• Last Update Posted (Estimate): July 26, 2016
• Last Update Submitted That Met QC Criteria: July 22, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: SBNK-2016-015-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes