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Cyclophosphamide

Bendamustine Hydrochloride

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Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide \[1.5 g/m\^2 x 1 day Intravenous (IV)\] or Bendamustine \[120 mg/m\^2 x 2 days Intravenous (IV)\] is administered as Pre-treatment medication of CD19-CAR-T.

Cyclophosphamide or Bendamustine

CD19-CAR-T \[1 x 10\^5 cells/kg x 1 day and 2 x 10\^5 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level -1

CD19-CAR-T \[1/3 x 10\^6 cells/kg x 1 day and 2/3 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 1

CD19-CAR-T \[1 x 10\^6 cells/kg x 1 day and 2 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 2

CD19-CAR-T \[1/3 x 10\^7 cells/kg x 1 day and 2/3 x 10\^7 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 3

Ken Ohmine, MD, PhD

Keiya Ozawa, MD, PhD

The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.

Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1：1/3 dose, Day 2：2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing.

This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects.

The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with "Revised response criteria malignant lymphoma", at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.

Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen

Confirm the toxicity profile with CTCAE ver4.0.

Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.

Confirm replication competent retrovirus (RCR) by PCR.

Confirm clonality by linear amplification mediated (LAM)-PCR.

Transduction efficiency, viability, sterility and potency.

Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).

Confirm the state of immune mechanism by flow cytometry.

Takara Bio Inc.

Jichi Medical University

Professor

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

0.3 to 3 x 10\^6 autologous CD19-CAR-T cells/kg per patient will be administered intravenously after a conditioning chemotherapy with cyclophosphamide.

cohort -1: 3×10\^5 cells/kg cohort 1: 1×10\^6 cells/kg cohort 2: 3×10\^6 cells/kg.

Phase-I portion:

Cyclophosphamide is administered for conditioning medication of TBI1501, that is CD19-CAR-T cells, (cohort -1: 3×10\^5 cells/kg, cohort 1: 1×10\^6 cells/kg, cohort 2: 3×10\^6 cells/kg).

Phase-II portion:

Recommended dose of Phase-II part will be administered. Cyclophosphamide will be administered as conditioning. The end of study will be Week 52 after administration of TBI-1501.

TBI-1501

Evaluate the safety (P-I), pharmacokinetics and anti-tumor effect of immunotherapy of autologous T cells genetically modified to express anti-CD19 chimeric antigen receptor (CAR) (TBI-1501) for relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia.

Enroll patients after confirming eligibility. Following enrollment, peripheral blood mononuclear cells and blood plasma will be obtained from each subject by apheresis to start the manufacturing of TBI-1501.

Before TBI-1501 administration, it is necessary to pass the quality tests. Subject will be hospitalized from Day -3 to Day 28, and administered Cyclophosphamide (1,000 mg/m2/day×2 days) on Day -3 and Day -2.

Peripheral blood will be collected from a subject after obtaining a written informed consent. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using retroviral vector.

Cyclophosphamide will be administered after obtaining a written informed consent and completing registration.

CD19-CAR-T will be administered in the split dose. Phase 2 recommended dose will be applied for phase 1 portion. The investigator assesses efficacy of CD19-CAR-T in accordance with study-specific criteria, at 8 week after the infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the infusion of CD19-CAR-T in reference to guidelines of FDA.

Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia

A Multicenter Phase I/II Study for Relapsed or Refractory CD19+ B-acute Lymphoblastic Leukemia

Adverse event (frequency, seriousness, duration, causality, severity, classification), mortality, severe adverse event, discontinuation due to adverse event.

Complete Remission (CR)+Complete Remission with Incomplete Blood Count Recovery (CRi) , as determined by assessments of peripheral blood and bone marrow.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes	NCT02134262	Relapsed or Ref...	Cyclophosphamid... Dose Level -1 Dose Level 1 Dose Level 2 Dose Level 3	20 Years - 70 Years	Jichi Medical University
Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia	NCT03155191	Lymphoblastic L...	TBI-1501	16 Years -	Takara Bio Inc.

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