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

Official title

Pragmatic Clinical Trial of CD19 and CD22 CAR T-cell Sequential Therapy Versus Single CD19 CAR T-cell Bridging to Transplantation for Patients With Refractory or Relapsed B-cell Acute Lymphoblastic Leukemia

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.

Interventions

• Drug CD19 CAR T-cell
  Murine-derived CD19 CAR T cells
• Drug CD22 CAR T cells
  humanized CD22 CAR T cells
• Procedure hematopoietic stem-cell transplantation
  allo-HSCT

Primary outcome measures

• 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) [Time frame: 2-year EFS rate]

Secondary outcome measures (9)

• ORR in Sequential CAR group and CAR+HSCT group [Time frame: 3 months (± 1 week) ORR]
• DOR in Sequential CAR group and CAR+HSCT group [Time frame: from enrollment to the end of treatment at 15 years]
• OS in Sequential CAR group and CAR+HSCT group [Time frame: from enrollment to the end of treatment at 15 years]
• Adverse events (AEs) in Sequential CAR group and CAR+HSCT group [Time frame: from enrollment to the end of treatment at 2 years]
• Levels of CD19 and CD22 CAR-T cells in Sequential CAR group [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 [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 [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 [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 [Time frame: from enrollment to the end of treatment at 15 years]

Eligibility criteria

Inclusion criteria

• Only patients who meet all the following criteria can be included in the group:

• 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);
• Age from 1 to 70 years old;
• No serious allergic constitution;
• Eastern Cooperative Oncology Group (ECOG) performance status (Oken et al., 1982) score 0 to 2;
• Have life expectancy of at least 60 days based on investigator's judgement;
• 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:

• Intracranial hypertension or unconscious;
• Acute heart failure or severe arrhythmia;
• Acute respiratory failure;
• Other types of malignant tumors;
• Diffuse intravascular coagulation;
• Serum creatinine and/or blood urea nitrogen over 1.5 times the normal value;
• Sepsis or other uncontrolled infection;
• Uncontrolled diabetes mellitus;
• Severe psychological disorder;
• Obvious cranial lesions by cranial MRI;
• More than 20 leukemic cells/μL in cerebrospinal fluid;
• More than 30% leukemic cells in the peripheral blood;
• Organ recipients;
• Pregnant or breastfeeding;
• Active, uncontrolled infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or treponema pallidum (TP).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Beijing GoBroad Hospital — Beijing

Identifiers

NCT: NCT06343090 · BJGBYY-IIT-LCYJ-2023-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗