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

Sponsor

University Health Network, Toronto (Other)

Overall Status

Recruiting

CT.gov ID

NCT05963217

Collaborator

Takara Bio Inc. (Industry)

Enrollment

Location

Arm

28.2

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Relapsed or Refractory CD19+ B-cell Lymphoma Relapsed or Refractory Chronic Lymphocytic Leukemia Relapsed or Refractory Small Lymphocytic Lymphoma	Biological: TBI-2001 Drug: Cyclophosphamide Drug: Fludarabine	Phase 1

Detailed Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

19 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Jul 26, 2023

Anticipated Primary Completion Date :

Nov 30, 2024

Anticipated Study Completion Date :

Nov 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental: Dose Level 1 to 3 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 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. Drug: Cyclophosphamide IV Cyclophosphamide (for 3 days) will be administered as conditioning before cell infusion with TBI-2001. Drug: Fludarabine IV Fludarabine (for 3 days) will be administered as conditioning before cell infusion with TBI-2001.

Arm

Intervention/Treatment

Experimental: Experimental: Dose Level 1 to 3

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

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.

Drug: Cyclophosphamide

IV Cyclophosphamide (for 3 days) will be administered as conditioning before cell infusion with TBI-2001.

Drug: Fludarabine

IV Fludarabine (for 3 days) will be administered as conditioning before cell infusion with TBI-2001.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Persistence of TBI-2001 [One year]
Percentage of CAR T in peripheral blood and bone marrow using PCR and Flow cytometry.
Minimal residual disease (MRD) negative rate (in CLL patients) [One year]
MRD negative rate

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.