Study of TBI-2001(Autologous CD19 Specific Chimeric Antigen Receptor (CAR) Gene-transduced T Lymphocytes) for Relapsed or Refractory CD19+ B-cell Lymphoma, CLL/SLL

Study Overview
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Brief Summary
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This is a Phase 1/1b, open-label, dose-escalation study to evaluate the safety and the efficacy of anti-CD19 chimeric antigen receptor (CAR) (TBI-2001) for relapsed or refractory CD19+ B-cell lymphoma Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL).

Detailed Description
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TBI-2001 is a next-generation CAR-T product including costimulatory sequences that lead to the activation of cytokine-related JAK/STAT signaling pathways. This is a first-in-human study of TBI-2001 and will follow a 3+3 design of dose-escalation cohorts. Additional subjects will be treated with TBI-2001 at the determined recommended phase 2 dose (RP2D) following cyclophosphamide and fludarabine pre-treatment. Long-term follow-up is conducted for 5 years following the infusion of TBI-2001

Official Title
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Phase I/Ib Study of TBI-2001 for Patients With Relapsed or Refractory CD19+ B-cell Lymphoma, Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

Conditions
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Relapsed or Refractory CD19+ B-cell Lymphoma, Relapsed or Refractory Chronic Lymphocytic Leukemia, Relapsed or Refractory Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: TBI-2001
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically or cytologically confirmed CD19 positive B cell Non-Hodgkin Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), or Small Lymphocytic Lymphoma (SLL) who have received at least 2 prior therapies. Phase Ib cohort will enroll CLL/SLL patients only. ECOG Performance Status 0 or 1. Age ≥18 years at time of consent. Life expectancy greater than 4 months. No anti-cancer chemotherapy, radiation therapy or immunotherapy within 2 weeks prior to apheresis for generation of TBI-2001. Patients must have adequate key organ function (bone marrow, heart, lung, liver, renal, etc) Consent must be appropriately obtained in accordance with applicable local and regulatory requirements. The treating investigator should consider the patient to have disease that is incurable, and that the patient would be a reasonable candidate for future treatment with TBI-2001 within the next 3 months Exclusion Criteria: Uncontrolled intercurrent illnesses or medical conditions that may interfere with trial participation. Active or prior documented autoimmune disease within the past 2 years. History of primary immunodeficiency. History of organ transplant that requires use of immunosuppressive medications. History hypersensitivity to components of manufacture or excipients of investigational drug. Untreated central nervous system (CNS) metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids. Other invasive malignancy within 2 years except for noninvasive malignancies Current or prior use of immunosuppressive medication within 14 days before apheresis. Any condition that, in the opinion of the investigator, would interfere with the evaluation of TBI-2001 or interpretation of subject safety or study results. Known history of untreated active tuberculosis. HIV positivity. Active HTLV or syphilis infection. Active hepatitis B or active hepatitis C. Subjects with a negative PCR assay for viral load for hepatitis B or C are permitted. Pregnant or lactating women. Received allogeneic-HSCT. Any prior CD19 directed therapy.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Dose Level 1 to 3<br>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 and fludarabine. | Biological: TBI-2001<br>* Phase-I portion: cohort 1: 3×10^5 cells/kg, cohort 2: 1×10^6 cells/kg, cohort 3: 3×10^6 cells/kg). Phase-Ib portion: The dose of Phase-Ib will be determined during the phase I portion.<br>Drug: Cyclophosphamide<br>* IV Cyclophosphamide (for 3 days) will be administered as conditioning before cell infusion with TBI-2001.<br>Drug: Fludarabine<br>* IV Fludarabine (for 3 days) will be administered as conditioning before cell infusion with TBI-2001.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of TBI-2001 | Dose Limiting Toxicities (DLTs) | One month | 
| Safety of TBI-2001 | Adverse event (AEs) | One year | 
| Safety of TBI-2001 | Laboratory testing- RCR appearance and Clonality | One year | 
| Recommended phase 2 dose (RP2D) of TBI-2001 | RP2D to be determined during the dose escalation cohort | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of TBI-2001; Overall Response Rate (ORR) | Overall Response Rate (ORR) (Complete Response (CR)+Partial Response(PR)) | One year | 
| Efficacy of TBI-2001; Durable Response Rate (DRR) | Durable Response Rate (DRR) as defined as CR or PR sustained for at least 6 months | One year | 
| Efficacy of TBI-2001; Progression free survival (PFS) | Progression free survival | One year | 
| Efficacy of TBI-2001; Overall survival (OS) | Overall survival | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, CD19+ B-cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, SLL, Lymphoma, TBI-2001, Anti-CD19 CAR Expressing T cell Therapy, CD19 CAR Gene-Transduced Lymphocyte, Adoptive Immunotherapy, Genetically Engineered Lymphocyte Therapy, Retroviral Vector, Neoplasms by Histologic Type, Neoplasms, Neoplasms, Experimental, Immune System Diseases, Chimeric Antigen Receptor