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CTLA-4 and PD-1 Antibodies Expressing EGFR-CAR-T Cells for EGFR Positive Advanced Solid Tumor

Phase 1
Conditions
Advanced Solid Tumor
Interventions
Biological: anti-CTLA-4/PD-1 expressing EGFR-CAR-T
Registration Number
NCT03182816
Lead Sponsor
Shanghai Cell Therapy Research Institute
Brief Summary

This is a single-arm, open-label, one center clinical study, to determine the safety and efficacy of infusion of autologous T cells engineered to express immune checkpoint antibodies (CTLA-4 and PD-1) and chimeric antigen receptor targeting epidermal growth factor receptor (EGFR-CAR) in adult patients with EGFR positive, advanced recurrent or refractory malignant solid tumors.

Detailed Description

This study will be conducted using a phase I/II trial design to assess the efficacy and safety of the CTLA-4 and PD-1 antibodies expressing EGFR-CAR-T for patients with EGFR positive advanced recurrent or refractory malignant solid tumors. EGFR-CAR-T can specificly and effectively kill the EGFR positive cancer cells, CTLA-4 and PD-1 antibodies are secreted from the CAR-T cells could improve immunosuppression microenvironment, new CAR-T cells contain the advantages of CAR-T and immune checkpoint inhibitor, which is a promising therapeutic method for advanced solid tumors.

The new CAR-T therapy is applied to clinical practice as bellow. T cells are prepared from peripheral blood mononuclear cells (PBMC) by leukapheresis, then activated and engineered to express CTLA-4 and PD-1 antibodies and chimeric antigen receptor targeting EGFR. Cells are proliferated in culture and returned to the patients by venous transfusion therapy. A total of 40 patients may be enrolled in the study. The total duration of the study is expected to be approximately 24 months.

Recruitment & Eligibility

Status
UNKNOWN
Sex
All
Target Recruitment
40
Inclusion Criteria
  1. Patients with relapsed or refractory advanced solid malignancies (diagnosed by histology or cytology detection).
  2. Progressive disease and no response after at least second-line therapy.
  3. Gender unlimited, age from 18 years to 80 years.
  4. Life expectancy ≥3 months.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  6. Adequate venous access for peripheral blood mononuclear cell (PBMC) apheresis, and no other contraindications.
  7. Immunohistochemistry (IHC) score of EGFR on tumor tissue ≥1+.
  8. Adequate hepatic function, renal function and bone marrow function (withhin 7 days before enrollment): white blood cell (WBC) ≥3.0×10^9/L; platelet ≥100×10^9/L; hemoglobin ≥90 g/L; lymphocyte ≥0.7×10^9/L; total bilirubin ≤2 times the upper limit of the normal value; alanine aminotransferase and aspartate transaminase(ALT and AST) ≤2.5 times the upper limit of the normal value; serum creatinine ≤1.5 times the upper limit of the normal value.
  9. There is no other treatments (chemotherapy, radiotherapy, etc.) within four weeks before enrollment.
  10. There is at least one measurable tumor lesion.
  11. Patients have adequate ability to understand, sign informed consents and take part in the clinical research voluntarily.
  12. Female patients in child bearing period must have evidence of negative pregnancy test, and agree to take effective contraceptive measures until 4 months after cells infusion.
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Exclusion Criteria
  1. Patients with two or more kinds of tumors.
  2. Patients with active viral or bacterial infection, and have failed to be controlled by anti-infective treatment.
  3. Patients with seropositive reponse of Human immunodeficiency virus (HIV) and syphilis, or fail to control the hepatitis B virus or hepatitis C virus infection.
  4. Patients with active rheumatic diseases, organ transplantation and other diseases affecting the immune system seriously.
  5. Patients with severe heart and lung dysfunction.
  6. Patients with severe chronic diseases of kidney, liver and other important organs.
  7. Patients with any other serious illnesse that the investigators consider it will may affect the patient's treatments, follow-up or assessment, including any uncontrolled clinically significant neurological or psychiatric disorders, immunoregulatory diseases, metabolic diseases, infectious diseases and so on.
  8. Patients who take part in clinical trials of other drugs or biological therapy at present or within 30 days before enrollment.
  9. Patients who need long-term use of immunosuppressive drugs or patients who are undergoing treatment of autoimmune diseases.
  10. Patients who need long-term use of glucocorticoid.
  11. Women patients in gestation period or suckling period.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
anti-CTLA-4/PD-1 expressing EGFR-CAR-Tanti-CTLA-4/PD-1 expressing EGFR-CAR-TThis study have only one arm that is anti-CTLA-4/PD-1 expressing EGFR-CAR-T group. All patients with advanced solid tumor will take part in the screening, who matching all the conditions will be chosen for the treatment using CTLA-4 and PD-1 antibodies expressing EGFR-targeted CAR-T cells. New CAR-T cells are cultured from PBMC and returned to the patients by venous transfusion.
Primary Outcome Measures
NameTimeMethod
Incidence of treatment-related adverse events as assessed by CTCAE v4.02 years

Determine treatment-related adverse events of the immunotherapy with common toxicity criteria for adverse effects (CTCAE) version 4.0.

Secondary Outcome Measures
NameTimeMethod
The response evaluation of of the treatment for advanced solid tumors2 years

The efficacy of the treatment is assessed according to the response evaluation criteria in solid tumor version 1.1 (RECIST1.1), which is defined as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).

Overall survival2 years

Overall survival is defined as the time from the day in which the patient is enrolled to the date on which the patient dies for any cause.

Progression free survival2 years

Progression free survival is defined as the time from the day in which the patient is enrolled to the date on which tumor progresses or the date on which the patient dies for any cause.

Trial Locations

Locations (1)

Ningbo No.5 Hospital (Ningbo Cancer Hospital)

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Ningbo, Zhejiang, China

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