Study of TBI-1301 (NY-ESO-1 T Cell Receptor Gene Transduced Autologous T Lymphocytes) in Patients With Synovial Sarcoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and the efficacy of TBI-1301 for NY-ESO-1 expressing synovial sarcoma when administered following cyclophosphamide pre-treatment.

Detailed Description
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Following pre-treatment with cyclophosphamide, NY-ESO-1-specific T cell receptor (TCR) gene transduced T lymphocytes are transferred to human leukocyte antigen (HLA)-A*02:01 or HLA-A*02:06 positive patients with synovial sarcoma expressing NY-ESO-1, which are surgically unresectable and refractory to anthracycline therapy. The primary objective is to evaluate the safety in the phase 1 and the efficacy in the phase 2.

Official Title
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Multi-center Phase I/II Study of NY-ESO-1 T Cell Receptor Gene Transferred T Lymphocytes in Patients With Synovial Sarcoma

Conditions
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Synovial Sarcoma

Intervention / Treatment
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* Biological: TBI-1301
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed synovial sarcoma Surgically unresectable tumor Progressing or recurrent synovial sarcoma which has been treated with 1-4 regimens of systemic chemotherapies including anthracycline HLA-A*02:01 or HLA-A*02:06 positive Tumor that express NY-ESO-1 by immunohistochemistry ≥ 18 years of age Measurable lesions that are evaluable by the RECIST ver1.1 ECOG Performance Status of 0, 1 or 2 No treatment such as chemotherapy and be expected to recover fully from the previous treatment at the time of the lymphocytes collection for manufacturing Life expectancy ≥ 16 weeks after consent No severe damage on the major organs (bone marrow, heart, lung, liver, kidney, etc) and meet the following lab value criteria; Total bilirubin ≤ 1.5 x upper limit of normal (ULN); AST(GOT), ALT(GPT) < 3.0 x ULN; Creatinine < 1.5 x ULN; 2,500/μL < WBC ≤ULN; Hemoglobin ≥ 8.0g/dL; Platelets ≥ 75,000/μL Patients must be able to understand the study contents and to give a written consent at his/her free will. Additionally, if patients are below 20 years of age, proxies must be able to give a written consent. Exclusion Criteria: Patients with the following conditions are excluded from the study; Unstable angina, cardiac infarction, or heart failure; Uncontrolled diabetes or hypertension; Active infection; Obvious interstitial pneumonia or lung fibrosis by chest X-ray; Active autoimmune disease requiring steroids or immunosuppressive therapy. Active metastatic tumor cell invasion into CNS Active multiple cancer Positive for HBs antigen or HBV-DNA observed in serum Positive for HCV antibody and HCV-RNA observed in serum Positive for antibodies against HIV or HTLV-1 Left Ventricular Ejection Fraction (LVEF) ≤ 50% History of serious hypersensitivity reactions to bovine or murine derived substances. History of hypersensitivity reaction to ingredients or excipients of investigational drugs used in this study History of hypersensitivity reaction to antibiotics used in manufacturing for the investigational drug used in this study. Pregnant females, lactating females (except when they cease and do not resume lactation) or female and male patients who cannot agree to practice the adequate birth control from the consent to 6 months after infusion of the investigational drug. Clinically significant systemic illness that in the judgment of the PI or sub-investigator would compromise the patient's ability to tolerate protocol therapy or significantly increase the risk of complications.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Split dose of 5x10^9 TBI-1301<br>Split dose of 5x10^9 TBI-1301 will be administered intravenously for 2 days following cyclophosphamide pre-treatment 750 mg/m2/d for 2 days. | Biological: TBI-1301<br>* Split dose of TBI-1301 is administered intravenously for 2 days following cyclophosphamide pre-treatment.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1301.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase I) Adverse event, mortality, severe adverse event, discontinuation due to adverse event, laboratory test values | Confirm the toxicity profile, which is measured by the degree of grade and seriousness, duration, causality, classification, etc. of the adverse events. | 52 weeks | 
| (Phase I) Appearance of replication competent retrovirus (RCR) by PCR | Confirm that no replication competent retrovirus observed. | 52 weeks | 
| (Phase I) Appearance of clonality by linear amplification mediated (LAM)-PCR | Confirm that no clonality is observed. | 52 weeks | 
| (Phase I) Blood kinetics of TBI-1301 by realtime-PCR | Evaluate persistence and expansion of transferred TBI-1301. | 52 weeks | 
| (Phase II) Overall response rate | Evaluate response rate by measuring response using RECIST v1.1 and irRECIST | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase I) Objective response rate | Evaluate response rate by measuring response using RECIST v1.1 and irRECIST | 52 weeks | 
| (Phase I/II) Progression free rate | Evaluate progression free rate by measuring response using RECIST v1.1 and irRECIST | 12 weeks | 
| (Phase I/II) Progression free survival | Evaluate progression free survival | 52 weeks | 
| (Phase I/II) Overall survival | Evaluate overall survival | 52 weeks | 
| (Phase II) Adverse event, mortality, severe adverse event, discontinuation due to adverse event, laboratory test values | Confirm the toxicity profile, which is measured by the degree of grade and seriousness, duration, causality, classification, etc. of the adverse events. | 52 weeks | 
| (Phase II) Appearance of RCR | Confirm that no replication competent retrovirus observed. | 52 weeks | 
| (Phase II) Appearance of clonality (LAM-PCR) | Confirm that no clonality is observed. | 52 weeks | 
| (Phase II) Blood kinetics of TBI-1301 by realtime-PCR | Evaluate persistence and expansion of transferred TBI-1301. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adoptive cell transfer, Cell therapy, Immunotherapy, NY-ESO-1, T cell receptor gene therapy, Synovial sarcoma