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This is a single-centre, phase I study to determine the efficacy and safety of CAR T-cell therapy in patients with high-risk T-ALL, refractory or relapsed T-ALL.

CAR T-cell therapy

Allen Yeoh, M.D

Zhiwei Chen, BSc.

Bernice Oh, M.D

Noriko Shimasaki, M.D, PhD

Michelle Poon, M.D

Esther Chan, M.D

Elaine Coustan-Smith, MS

Dario Campana, M.D, PhD

The objective of this study is to assess the safety and efficacy of anti-CD7 CAR T-cells in patients with refractory or relapsed T-lineage acute lymphoblastic leukemia (T-ALL).

A major obstacle to the development of effective CAR T-cells for T-cell malignancies is that the surface marker profile of malignant T-cells largely overlaps that of activated T lymphocytes. We developed a CAR T-cell approach that targets CD7, a T-cell marker highly expressed in all cases of T-cell ALL, including ETP-ALL. Its expression is also highly stable even in T-ALL cells exposed to chemotherapy. To prevent fratricide effect of the T cells, surface CD7 expression are effectively downregulated with the expression of an anti-CD7 Protein Expression Blocker (PEBL). Patients will receive anti-CD7 PEBL CART-cells. This will allow targeting the entire leukemia cell population to induce deeper and more durable remissions.

CARTALL: Chimeric-Antigen Receptor (CAR) T-Cell Therapy for Relapsed/ Refractory T-Lineage Acute Lymphoblastic Leukaemia

Anti-CD7 Protein Expression Blocker (PEBL) Chimeric-Antigen Receptor (CAR) T-Cell Therapy for Relapsed/ Refractory T-Lineage Acute Lymphoblastic Leukaemia (CARTALL)

MRD levels will be determined by flow cytometry. The target sensitivity of flow MRD is \<0.01% when available.

MRD levels will be determined by molecular based MRD by Ig/TCR. PCR and oncogene fusion transcript (OFT).

Flow cytometry will be performed on bone marrow, peripheral blood and CSF samples at multiple study time points following CAR T cell infusion

National University Hospital, Singapore

Neoplasms, Experimental

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Immunomodulating Agents

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
CARTALL: Chimeric-Antigen Receptor (CAR) T-Cell Therapy for Relapsed/ Refractory T-Lineage Acute Lymphoblastic Leukaemia	NCT05043571	Lymphoblastic L... Lymphoblastic L... Lymphoblastic L... Lymphoblastic L... CAR CAR T-Cell-Rela... Refractory Leuk...	CAR T-cell ther...	6 Months - 65 Years	National University Hospital, Singapore
Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia	NCT03155191	Lymphoblastic L...	TBI-1501	16 Years -	Takara Bio Inc.

Spots Global Cancer Trial Database for lymphoblastic leukemia, acute adult