Investigator Initiated Phase 1 Study of TBI-1301

Multi-center, Investigator Initiated Phase 1 Study of NY-ESO-1 Specific TCR Gene Transferred T Lymphocytes With Solid Tumors

Following pre-treatment with cyclophosphamide and/or fludarabine, NY-ESO-1-specific TCR gene transduced T lymphocytes are transferred to the patients with NY-ESO-1-expressing solid tumors.

Study Overview

• Status: Unknown
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: TBI-1301; Drug: Fludarabine

Detailed Description

Following pre-treatment with cyclophosphamide alone or in combination with fludarabine, NY-ESO-1-specific TCR gene transduced T lymphocytes are transferred to HLA-A*02:01 or HLA-A*02:06 positive patients with solid tumors which are 1) unresectable, refractory to standard therapy (chemotherapy, radiotherapy, etc), and 2) NY-ESO-1-expressing. The primary objective is to evaluate the safety and in vivo kinetics, and the secondary is to evaluate clinical effect.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Mie
    • Tsu, Mie, Japan
      • Mie University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed solid tumors
2. Solid tumor, which is unresectable, refractory to standard therapy (chemotherapy, radiotherapy, etc)
3. HLA-A*02:01 or HLA-A*02:06 positive
4. NY-ESO-1-expression by PCR or immunohistochemistry
5. ECOG Performance Status, 0 or 1
6. Age >=20 years on consent
7. No treatment (surgery, chemotherapy, radiotherapy, etc.) and expected sufficient recovery from the treatment at the time of the lymphocytes collection for gene transfer.
8. Life expectancy >=16 weeks after consent

9. 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
10. Ability to understand the study contents and to give a written consent at his/her free will.

Exclusion Criteria:

1. 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.
2. Serious hypersensitivity
3. Tumor cell invasion into CNS
4. Active multiple cancer
5. Positive for HBs antigen or HBV-DNA observed in serum
6. Positive for HCV antibody and HCV-RNA observed in serum
7. Positive for antibodies against HIV or HTLV-1
8. Left Ventricular Ejection Fraction (LVEF): <= 50％
9. Percutaneous Oxygen saturation: < 94％
10. History of serious hypersensitivity reactions to bovine or murine derived substances.
11. History of hypersensitivity reaction to drugs used in this study.
12. Psychological disorder or drug dependency which may have impact on the consent.
13. 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
14. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose TBI-1301 with pre-treatment 1; TBI-1301(5*10^8) single-dose administration with pre-treatment of cyclophosphamide alone.	Drug: Cyclophosphamide; Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1301.; Other Names: Endoxan; Drug: TBI-1301; TBI-1301(5*10^8 or 5*10^9) is administered.; Other Names: NY-ESO-1-specific TCR gene transduced T lymphocytes
Experimental: High dose TBI-1301 with pre-treatment 1; TBI-1301(5*10^9) single-dose administration with pre-treatment of cyclophosphamide alone.	Drug: Cyclophosphamide; Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1301.; Other Names: Endoxan; Drug: TBI-1301; TBI-1301(5*10^8 or 5*10^9) is administered.; Other Names: NY-ESO-1-specific TCR gene transduced T lymphocytes
Experimental: High dose TBI-1301 with pre-treatment 2; TBI-1301(5*10^9) single-dose administration with pre-treatment of cyclophosphamide and fludarabine.	Drug: Cyclophosphamide; Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1301.; Other Names: Endoxan; Drug: TBI-1301; TBI-1301(5*10^8 or 5*10^9) is administered.; Other Names: NY-ESO-1-specific TCR gene transduced T lymphocytes; Drug: Fludarabine; Fludarabine (20mg/m2 x 5 days Intravenous(IV)) is administered as pre-treatment medication of TBI-1301 in combination with cyclophosphamide.; Other Names: Fludara
Experimental: TBI-1301 with pre-treatment 1 or 2; Arm1, 2 or 3, which is considered as optimal.	Drug: Cyclophosphamide; Cyclophosphamide (750mg/m2/day x 2 days Intravenous (IV)) is administered as pre-treatment medication of TBI-1301.; Other Names: Endoxan; Drug: TBI-1301; TBI-1301(5*10^8 or 5*10^9) is administered.; Other Names: NY-ESO-1-specific TCR gene transduced T lymphocytes; Drug: Fludarabine; Fludarabine (20mg/m2 x 5 days Intravenous(IV)) is administered as pre-treatment medication of TBI-1301 in combination with cyclophosphamide.; 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.	4 weeks
Appearance of replication competent retrovirus by PCR	Confirm no replication competent retrovirus observed.	4 weeks
Appearance of clonality by LAM-PCR	Confirm no clonality is observed.	4 weeks
Kinetics of TBI-1301 in blood by realtime-PCR	Evaluate persistence and expansion of transferred TBI-1301.	8 weeks

Collaborators and Investigators

• Sponsor: Mie University
• Collaborators: Fiverings Co., Ltd.; Shionogi; Takara Bio Inc.; Statcom Co. Ltd.
• Investigators: Study Chair: Hiroshi Shiku, M.D., Ph.D., Department of Immuno-Gene Therapy, Mie University, Graduate School of Medicine Mie University Hospital; Principal Investigator: Shinichi Kageyama, M.D., Ph.D., Department of Immuno-Gene Therapy, Mie University, Graduate School of Medicine Mie University Hospital

Publications and helpful links

General Publications

• Ishihara M, Kitano S, Kageyama S, Miyahara Y, Yamamoto N, Kato H, Mishima H, Hattori H, Funakoshi T, Kojima T, Sasada T, Sato E, Okamoto S, Tomura D, Nukaya I, Chono H, Mineno J, Kairi MF, Diem Hoang Nguyen P, Simoni Y, Nardin A, Newell E, Fehlings M, Ikeda H, Watanabe T, Shiku H. NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome. J Immunother Cancer. 2022 Jun;10(6):e003811. doi: 10.1136/jitc-2021-003811.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: February 12, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 19, 2015

Study Record Updates

• Last Update Posted (Actual): October 24, 2018
• Last Update Submitted That Met QC Criteria: October 22, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Immunotherapy; Ovarian cancer; Melanoma; Cell therapy; Head and neck cancer; Esophageal cancer; NY-ESO-1; Synovial sarcoma; Adoptive cell transfer; TCR gene therapy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 1301-01