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

Glioblastoma Multiforme Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02937844
• Other study ID #: SBNK-2016-016-01
• Status: Recruiting
• Phase: Phase 1
• First received: July 22, 2016
• Last updated: October 17, 2016
• Start date: July 2016
• Est. completion date: July 2019

Study information

• Verified date: October 2016
• Source: Beijing Sanbo Brain Hospital
• Contact: Zhixiong Lin, MD
• Phone: +86-10-13905918963
• Email: lzx1967[@]sina.com
• Is FDA regulated: No
• Health authority: China: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: July 2019
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme

Intervention

Biological:
• Anti-PD-L1 CSR T cells
Prescribed CSR T cells are infused intravenously to patients in a three-day split-dose regimen(day0,10%; day1, 30%; day2, 60%).

Drug:
• Cyclophosphamide
250 mg/m^2, d1-3
• Fludarabine
25mg/m^2, d1-3

Locations

Country	Name	City	State
China	Sanbo Brain Hospital Capital Medical University	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Beijing Sanbo Brain Hospital	Marino Biotechnology Co., Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Persistence of CSR T cells in patients		12 months	No
Primary	Number of Adverse Events related to CSR T cell infusion		2 years	Yes
Secondary	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	No
Secondary	Overall Survival Rate		2 years	No
Secondary	Progression-free Survival Rate		6 months	No