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Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme

Primary Purpose

Glioblastoma Multiforme

Status
Unknown status
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Anti-PD-L1 CSR T cells
Cyclophosphamide
Fludarabine
Sponsored by
Beijing Sanbo Brain Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 PD-L1 positive confirmed by IHC;
  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.

Sites / Locations

  • Sanbo Brain Hospital Capital Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Anti-PD-L1 CSR T cells

Arm Description

Patients will receive lymphodepletion chemotherapy consisting of fludarabine and cyclophosphamide, followed by intravenous infusion of autologous anti- PD-L1 CSR 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.

Outcomes

Primary Outcome Measures

Number of Adverse Events related to CSR T cell infusion

Secondary Outcome Measures

Treatment Responses Rate
Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease(SD), or progressive disease (PD).
Overall Survival Rate
Progression-free Survival Rate

Full Information

First Posted
July 22, 2016
Last Updated
October 17, 2016
Sponsor
Beijing Sanbo Brain Hospital
Collaborators
Marino Biotechnology Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT02937844
Brief Title
Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme
Official Title
A Safety and Efficacy Study of Autologous Chimeric Switch Receptor Engineered T Cells Redirected to PD-L1 in Patients With Recurrent Glioblastoma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Unknown status
Study Start Date
July 2016 (undefined)
Primary Completion Date
July 2018 (Anticipated)
Study Completion Date
July 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Beijing Sanbo Brain Hospital
Collaborators
Marino Biotechnology Co., Ltd.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
CAR T cell immunotherapy has achieved great success in CD19+ B-cell malignancies. Whether this new generation of cell-based immunotherapy can be applied to solid tumors remain to be investigated, partly due to hostile immune-suppressive tumor microenvironment which favors tumor growth but not immune system. Signaling pathway of programmed death 1 (PD-1) and its ligand PD-L1 plays an important role in suppressing immune response against tumors. PD-L1 is over-expressed in 88% of glioblastoma. We constructed a chimeric switch receptor (CSR) containing the extracellular domain of PD1 fused to the transmembrane and cytoplasmic domain of the costimulatory molecule CD28. CSR modified T cells are able to recognize PD-L1-expressing tumor cells and transduce signals to activate T cells, which results in tumor killing. A truncated EGFR (tEGFR) which lacks of the ligand binding domain and cytoplasmic kinase domain of wildtype EGFR is incorporated into the CSR vector and is used for in vivo tracking and ablation of CSR T cells when necessary. This pilot study is to determine the safety and efficacy of autologous CSR T cells in patients with recurrent glioblastoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Anti-PD-L1 CSR T cells
Arm Type
Experimental
Arm Description
Patients will receive lymphodepletion chemotherapy consisting of fludarabine and cyclophosphamide, followed by intravenous infusion of autologous anti- PD-L1 CSR 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.
Intervention Type
Biological
Intervention Name(s)
Anti-PD-L1 CSR T cells
Intervention Description
Prescribed CSR T cells are infused intravenously to patients in a three-day split-dose regimen（day0,10%; day1, 30%; day2, 60%）.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
250 mg/m^2, d1-3
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
25mg/m^2, d1-3
Primary Outcome Measure Information:
Title
Number of Adverse Events related to CSR T cell infusion
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Treatment Responses Rate
Description
Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease(SD), or progressive disease (PD).
Time Frame
4 weeks
Title
Overall Survival Rate
Time Frame
2 years
Title
Progression-free Survival Rate
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Persistence of CSR T cells in patients
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: abilities to understand and the willingness to provide written informed consent; patients are ≥ 18 and ≤ 70 years old; 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; Malignant cells are PD-L1 positive confirmed by IHC; karnofsky performance score (KPS) ≥ 60; life expectancy >3 months; 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; peripheral blood absolute lymphocyte count must be above 0.8×10^9/L; satisfactory heart functions; patients must be willing to follow the orders of doctors; 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: a prior history of gliadel implantation 4 weeks before this study start or antibody based therapies; HIV positive; hepatitis B infection or hepatitis C infection; history of autoimmune disease, or other diseases require long-term administration of steroids or immunosuppressive therapies; history of allergic disease, or allergy to CAR T cells or study product excipients; patients already enrolled in other clinical study; patients, in the opinion of investigators, may not be eligible or not able to comply with the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhixiong Lin, MD
Phone
+86-10-13905918963
Email
lzx1967@sina.com
Facility Information:
Facility Name
Sanbo Brain Hospital Capital Medical University
City
Beijing
ZIP/Postal Code
100093
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhixiong Lin, MD
Phone
+86-10-13905918963
Email
lzx1967@sina.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme

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