Treatment of Chemotherapy Refractory Human Epidermalgrowth Factor Receptor-2( HER-2) Positive Advanced Solid Tumors

Study Overview
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Brief Summary
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RATINALE: Placing a tumor antigen chimeric receptor that has been created in the laboratory into patient autologous T cells may make the body build immune response to kill cancer cells. PURPOSE: This clinical trial is to study genetically engineered lymphocyte therapy in treating patients with HER-2 positive advanced solid tumors,such as breast cancer, gastric cancer, hepatic carcinoma, endometrial cancer and ovary cancer.

Detailed Description
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PRIMARY OBJECTIVES: I.Determine the safety and feasibility of the chimeric antigen receptor T cells transduced with anti-HER-2 vector(referred to as CART-HER-2 cells). II.Determine duration of in vivo survival of CART-HER-2 cells. RT-PCR(reverse transcription polymerase chain reaction)analysis of whole blood will be used to detect and quantify survival of CART-HER-2 TCR zeta:CD137 and TCR(T-cell receptor) zeta cells over time. SECONDARY OBJECTIVES: I.For patients with detectable diseases, measure anti-tumor response due to CART-HER-2 cell infusions. II.Estimate relative trafficking of CART-HER-2 cells in tumor bed. III.Determine if cellular or humoral host immunity develops against the murine anti-HER-2, and assess correlation with loss of detectable CART-HER-2(loss of engraftment). IV.Determine the relative subsets of CART-HER-2 T cells (Tcm,Tem,and Treg). OUTLINE: Patients are assigned to 1 group according to order of enrollment. Patients receive anti-HER-2-CAR (coupled with CD137 and CD3 zeta signalling domains)vector-transduced autologous T cells on days 0,1, and 2 in the absence of unacceptable toxicity. After completion of study treatment, patients are followed intensively for 6 months, every 3 months for 2 years, and annually thereafter for 13 years. Estimate relative trafficking of CART-HER-2 cells in peripheral blood.

Official Title
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Clinical Study of Chimeric HER-2 Antigen Receptor-modified T Cells in Chemotherapy Refractory HER-2 Advanced Solid Tumors

Conditions
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Advanced HER-2 Positive Solid Tumors, Chemotherapy Refactory, HER-2 Antibody Inhibitor Therapy Refactory

Intervention / Treatment
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* Biological: CART-HER-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chemotherapy refractory HER-2-positive breast cancer, gastric cancer, non-small cell lung cancer, and chemotherapy resistant or relapsed ovary cancer. Relapsed patients after anti-HER-2 using antibody or kinase inhibitor therapy. Patients must be 18 years of age or older. Patients must have an ECOG (Eastern Cooperative Oncology Group )performance status of 0-2. Patients must have evidence of adequate bone marrow reserve, hepatic and renal function as evidenced by the following laboratory parameters: Absolute neutrophil count greater than 1500/mm3. Platelet count greater than 100,000/mm3. Hemoglobin greater than 10g/dl (patients may receive transfusions to meet this parameter). Total bilirubin < 1.5 times upper limits of normal. Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m(2). Seronegative for HIV antibody. Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. Patients must be willing to practice birth control during and for four months following treatment.NOTE:women of child-bearing age must have evidence of negative pregnancy test. Patients must be willing to sign an informed consent. Exclusion Criteria: Patients with life expectancy less than 12 months will be excluded. Patients with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (> New York Heart Association Class II), or myocardial infarction within 6 months of study will be excluded. Patients with any of the following pulmonary function abnormalities will be excluded: FEV(forced expiratory volume), < 30% predicted; DLCO (diffusing capacity of lung for carbon monoxide) < 30% predicted (post-bronchodilator); Oxygen Saturation less than 90% on room air. Patients with severe liver and kidney dysfunction or consciousness disorders will be excluded. Pregnant and/or lactating women will be excluded. Patients with active infections, including HIV, will be excluded, due to unknown effects of the vaccine on lymphoid precursors. Patients with any type of primary immunodeficiencies will be excluded from the study. Patients requiring corticosteroids (other than inhaled) will be excluded. Patients with history of T cell tumors will be excluded. Patients who are participating or participated any other clinical trials in latest 30 days will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-tumor responses of CART-HER-2<br> | Biological: CART-HER-2<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Study related adverse events |  | Until week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-leukemia response to CART-HER-2 cell infusions |  | up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CART-HER-2, HER-2 positive, Advanced, Refactory, Solid tumors