Investigator Initiated Phase 1 Study of TBI-1201

Study Overview
=================
Brief Summary
-----------------
Following pre-treatment with cyclophosphamide and/or fludarabine, MAGE-A4-specific TCR gene transduced T lymphocytes are transferred to the patients with MAGE-A4-expressing solid tumors.

Detailed Description
-----------------
Following pre-treatment with cyclophosphamide alone or in combination with fludarabine, MAGE-A4-specific TCR gene transduced T lymphocytes are transferred to HLA-A*24:02 positive patients with solid tumors which are 1) unresectable, refractory to standard therapy (chemotherapy, radiotherapy, etc), metastatic or recurrent, and 2) MAGE-A4-expressing. The primary objective is to evaluate the safety and in vivo kinetics, and the secondary is to evaluate clinical effect.

Official Title
-----------------
Multi-center, Investigator Initiated Phase 1 Study of MAGE-A4 Specific TCR Gene Transferred T Lymphocytes With Solid Tumors

Conditions
-----------------
Solid Tumors

Intervention / Treatment
-----------------
* Drug: TBI-1201
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed solid tumors Solid tumor, which is unresectable , refractory to standard therapy (chemotherapy, radiotherapy, etc) , metastatic or recurrent HLA-A*24:02 positive MAGE-A4-expression by PCR or immunohistochemistry ECOG Performance Status, 0 or 1 Age >20 years on consent No treatment (surgery, chemotherapy, radiotherapy, etc.) and expected sufficient recovery from the treatment at the time of the lymphocytes collection for gene transfer. 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: WBC > 2,500/μL Hemoglobin > 8.0g/dL Platelets > 75,000/μL T. bilirubin < 1.5 x ULN AST(GOT)、ALT(GPT) < 3.0 x ULN Creatinine < 1.5 x ULN Ability to understand the study contents and to give a written consent at his/her free will. Exclusion Criteria: The following serious complications 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 Serious hypersensitivity Tumor cell invasion into CNS Active multiple cancer Positive for HBs antigen/antibody, HBc antibody, or HCV antibody, and virus DNA observed in serum, except for HBs antibody positive case who had vaccine injection before. Positive for antibodies against HIV or HTLV-1 Left Ventricular Ejection Fraction (LVEF): =< 50％ Percutaneous Oxygen saturation: < 94％ History of hypersensitivity reactions to bovine or murine derived substances. History of hypersensitivity reaction to drugs used in this study Psychological disorder or drug dependency which may have impact on the consent. Pregnant females, lactating females (except when they cease and don't resume lactation) or female and male patients who cannot agree to practice the adequate birth control after the consent during the study 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
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose TBI-1201 with pre-treatment 1<br>TBI-1201(5*10^8) single-dose administration with pre-treatment of cyclophosphamide alone. | Drug: TBI-1201<br>* TBI-1201(5*10^8 or 5*10^9) is administered.<br>* Other names: MAGE-A4-specific TCR gene transduced T lymphocytes;Drug: Cyclophosphamide<br>* Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1201<br>* Other names: Endoxan;|
| Experimental: High dose TBI-1201 with pre-treatment 1<br>TBI-1201(5*10^9) single-dose administration with pre-treatment of cyclophosphamide alone. | Drug: TBI-1201<br>* TBI-1201(5*10^8 or 5*10^9) is administered.<br>* Other names: MAGE-A4-specific TCR gene transduced T lymphocytes;Drug: Cyclophosphamide<br>* Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1201<br>* Other names: Endoxan;|
| Experimental: High dose TBI-1201 with pre-treatment 2<br>TBI-1201(5*10^9) single-dose administration with pre-treatment of cyclophosphamide and fludarabine. | Drug: TBI-1201<br>* TBI-1201(5*10^8 or 5*10^9) is administered.<br>* Other names: MAGE-A4-specific TCR gene transduced T lymphocytes;Drug: Cyclophosphamide<br>* Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1201<br>* Other names: Endoxan;Drug: Fludarabine<br>* Fludarabine (20mg/m2 x 5 days Intravenous(IV)) is administered as pre-treatment medication of TBI-1201 in combination with cyclophosphamide.<br>* Other names: Fludara;|
| Experimental: TBI-1201 with pre-treatment 1 or 2<br>Arm1, 2 or 3, which is considered as optimal. | Drug: TBI-1201<br>* TBI-1201(5*10^8 or 5*10^9) is administered.<br>* Other names: MAGE-A4-specific TCR gene transduced T lymphocytes;Drug: Cyclophosphamide<br>* Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1201<br>* Other names: Endoxan;Drug: Fludarabine<br>* Fludarabine (20mg/m2 x 5 days Intravenous(IV)) is administered as pre-treatment medication of TBI-1201 in combination with cyclophosphamide.<br>* Other names: Fludara;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and grade of adverse events (CTCAE) | Confirm the toxicity profile, which is measured by the degree of grade and seriousness, duration, causality, classification, etc. of the adverse events. | 8 weeks | 
| Appearance of replication competent retrovirus by PCR | Confirm no replication competent retrovirus observed | 8 weeks | 
| Appearance of clonality by LAM-PCR | Confirm no clonality is observed | 8 weeks | 
| Kinetics of TBI-1201 in blood by realtime-PCR and flow cytometry | Evaluate persistence and expansion of transferred TBI-1201 | 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adoptive cell transfer, Cell therapy, Immunotherapy, MAGE-A4, Esophageal cancer, Melanoma, Head and neck cancer, Ovarian cancer, TCR gene therapy