Clinical Trial of CD19 and CD22 CAR Sequential Therapy Versus Single CD19 CAR Bridging to HSCT for r/r B-ALL Patients

Beijing GoBroad Hospital353 enrolled

Overview

This is a multi-center, open-label, non-randomized, two-arm, non-inferior trial. Patients with r/r B-ALL would be assigned to the CD19 CAR and CD22 CAR T-cell sequential infusion group (Sequential CAR, Arm-1) and the CD19 CAR T-cell infusion bridging to hematopoietic stem cell transplantation group (CAR+HSCT, Arm-2), according their own discretion. Patients would be also allowed to assigned to the CD19 CAR T-cell infusion without consolidation therapies group (Single CAR, additional placebo arm) according their own discretion. The primary objective is to prospectively evaluate and compare the efficacy of CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT in the treatment of r/r B-ALL. The primary endpoint is event-free survival of children and adolescent and young adult (AYA) with r/r B-ALL a treated with CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. A total number of 353 subjects will be enrolled.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

353

Conditions

B-cell Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia, in Relapse

Eligibility

Sex: ALLMin age: 1 YearMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Only patients who meet all the following criteria can be included in the group: 1. Patients who were diagnosed as primary refractory or relapsed B-ALL. (Criterion-reference: NCCN, version 2.2023); All the patients matched the diagnostic criteria of ALL according to the NCCN guideline (≥20% bone marrow lymphoblasts on hematopathology review of bone marrow aspirate and biopsy materials, which were confirmed by comprehensive flow cytometric immunophenotyping, minimal residual disease analysis and karyotyping of G-banded metaphase chromosomes). Molecular characterization could be obtained via interphase fluorescence in situ hybridization (FISH) testing, reverse transcriptase polymerase chain reaction (RT-PCR) testing, comprehensive testing by next-generation sequencing (NGS) for gene fusions and pathogenic mutations, etc. Determination of the World Health Organization ALL subtypes and cytogenetic and clinical risk groups were also allowed. B-ALL patients who did not achieve a complete remission after previous therapy (including the various treatment response scenarios shown in Table 1), who did not achieve a complete remission after at least two lines of TKI agents (including the various treatment response scenarios shown in Table 1), or who had ≥1 relapses were defined as having refractory or relapsed disease. Patients who were diagnosed as CD19- and CD22-positive high-risk B-ALL with continuous positive minimal residual disease (MRD) for more than three months after last therapy were also eligible. Patients had positive CD19 and CD22 expression on leukemia blasts by FCM (\>80% CD19 and CD22 positive); 2. Age from 1 to 70 years old; 3. No serious allergic constitution; 4. Eastern Cooperative Oncology Group (ECOG) performance status (Oken et al., 1982) score 0 to 2; 5. Have life expectancy of at least 60 days based on investigator's judgement; 6. Voluntary informed consent is signed by self-aware patients aged 8-70 years and by legal representatives (guardians) of pediatric patients under 18 years of age. Exclusion Criteria: * Patients with at least one of the following conditions are excluded: 1. Intracranial hypertension or unconscious; 2. Acute heart failure or severe arrhythmia; 3. Acute respiratory failure; 4. Other types of malignant tumors; 5. Diffuse intravascular coagulation; 6. Serum creatinine and/or blood urea nitrogen over 1.5 times the normal value; 7. Sepsis or other uncontrolled infection; 8. Uncontrolled diabetes mellitus; 9. Severe psychological disorder; 10. Obvious cranial lesions by cranial MRI; 11. More than 20 leukemic cells/μL in cerebrospinal fluid; 12. More than 30% leukemic cells in the peripheral blood; 13. Organ recipients; 14. Pregnant or breastfeeding; 15. Active, uncontrolled infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or treponema pallidum (TP).

Outcomes

Primary Outcomes

EFS in CD19 CAR and CD22 CAR-T sequential infusion (Sequential CAR group) and CD19 CAR T-cell infusion bridging to HSCT (CAR+HSCT group)

Event-free survival (EFS) of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. EFS is defined as the time from CD19 CAR T-cell infusion to the earliest relapse, death from any cause, or treatment failure.

Time frame: 2-year EFS rate

Secondary Outcomes

ORR in Sequential CAR group and CAR+HSCT group

Overall response rate (ORR) includes minimal residual disease-negative CR, CRh, CRi, MLFS, aplastic marrow for blood and bone marrow; central nervous system (CNS) remission; CR for lymphomatous extramedullary disease at 3 months (± 1 week) post CD19 CAR T-cell infusion in patients treated by CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT.

Time frame: 3 months (± 1 week) ORR

DOR in Sequential CAR group and CAR+HSCT group

Duration of remission (DOR) of children and AYA with r/r B-ALL treated by CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. DOR is defined as the time interval from the earliest qualifying minimal residual disease-negative response \[i.e. CR, CRh, CRi, MLFS, or aplastic marrow (patients with blood and bone marrow disease), CNS remission (patients with CNS disease) and complete resolution of the lymphomatous enlargement by CT or PET-CT negative (for patients with a previous positive PET-CT) (patients with lymphomatous extramedullary disease)\] to the date of relapse or death from any cause.

Time frame: from enrollment to the end of treatment at 15 years

OS in Sequential CAR group and CAR+HSCT group

Overall survival (OS) of children and AYA with r/r B-ALL treated by CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. OS is defined as the time from CD19 CAR T-cell infusion to death from any cause.

Time frame: from enrollment to the end of treatment at 15 years

Adverse events (AEs) in Sequential CAR group and CAR+HSCT group

Total number, incidence and severity of adverse events (AEs) in patients of CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT in the treatment of r/r B-ALL. The AEs will be assessed according to the 2019 Consensus on Cytokine Release Syndrome and Immune-cell-associated Neurotoxicity published by the American Society of Transplantation and Cell Therapy (ASTCT), the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and EBMT 2019 consensus.

Time frame: from enrollment to the end of treatment at 2 years

Levels of CD19 and CD22 CAR-T cells in Sequential CAR group

The levels of CD19 and CD22 CAR-T cells in peripheral blood from patients treated by CD19 CAR and CD22 CAR T cell sequential infusions will be measured by flow cytometry.

Time frame: from CD19 CAR T-cell infusion to the end of treatment at 15 years

Levels of CD19 CAR-T cells in CAR+HSCT group

The levels of CD19 CAR-T cells in peripheral blood from patients in CAR+HSCT group will be measured by flow cytometry.

Time frame: from CD19 CAR T-cell infusion to the end of treatment at 15 years

Levels of CD19 and CD22 CAR transgene in Sequential CAR group

The levels of CD19 and CD22 CAR transgene in peripheral blood from patients treated by CD19 CAR and CD22 CAR T cell sequential infusions will be measured by quantitative polymerase chain reaction (qPCR).

Time frame: from CD19 CAR T-cell infusion to the end of treatment at 15 years

Levels of CD19 CAR transgene in CAR+HSCT group

The levels of CD19 CAR transgene in peripheral blood from patients in CAR+HSCT group will be measured by quantitative polymerase chain reaction (qPCR).

Time frame: from CD19 CAR T-cell infusion to the end of treatment at 15 years

Quantification of B cells in Sequential CAR group and CAR+HSCT group

Quantification of B cells in peripheral blood from patients treated by CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT will be measured by complete blood count and flow cytometry.

Time frame: from enrollment to the end of treatment at 15 years

Clinical Trial of CD19 and CD22 CAR Sequential Therapy Versus Single CD19 CAR Bridging to HSCT for r/r B-ALL Patients

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts