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

B-cell Acute Lymphoblastic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06343090
• Other study ID #: BJGBYY-IIT-LCYJ-2023-003
• Status: Recruiting
• Phase: N/A
• Start date: April 12, 2024
• Est. completion date: September 30, 2043

Study information

• Verified date: April 2024
• Source: Beijing GoBroad Hospital
• Contact: Tengyu Wang
• Phone: 86+18333186020
• Email: tengyu.wang[@]gohealtharo.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 353
• Est. completion date: September 30, 2043
• Est. primary completion date: December 1, 2042
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 39 Years

Eligibility

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 39 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 8-39 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).

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia, in Relapse
• B-cell Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Refractory Acute Lymphoid Leukemia

Intervention

Drug:
• CD19 CAR T-cell
Murine-derived CD19 CAR T cells
• CD22 CAR T cells
humanized CD22 CAR T cells

Procedure:
• hematopoietic stem-cell transplantation
allo-HSCT

Locations

Country	Name	City	State
China	Beijing GoBroad Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Beijing GoBroad Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	EFS in CD19 CAR T-cell infusion without consolidation therapies (Single CAR group)	EFS of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR T-cell infusion without consolidation therapies.	2-year EFS rate
Other	DOR in Single CAR group	DOR of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR T-cell infusion without consolidation therapies.	from enrollment to the end of treatment at 15 years
Other	OS in Single CAR group	OS of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR T-cell infusion without consolidation therapies.	from enrollment to the end of treatment at 15 years
Other	ORR in Single CAR group	ORR at 3 months (± 1 week) post CD19 CAR T-cell infusion, of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR T-cell infusion without consolidation therapies.	3 months (± 1 week) ORR
Other	Adverse events (AEs) in Single CAR group	Total number, incidence and severity of adverse events (AEs) in patients treated by CD19 CAR T-cell infusion without consolidation therapies 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.	from enrollment to the end of treatment at 2 years
Other	Levels of CD19 CAR-T cells in Single CAR group	The levels of CD19 CAR-T cells in peripheral blood from patients treated by CD19 CAR T-cell infusion without consolidation therapies will be measured by flow cytometry.	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Other	Levels of CD19 CAR transgene in Single CAR group	The levels of CD19 CAR transgene in peripheral blood from patients treated by CD19 CAR T-cell infusion without consolidation therapies will be measured by quantitative polymerase chain reaction (qPCR).	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Other	Quantification of B cells in Single CAR group	Quantification of B cells in peripheral blood from patients treated by CD19 CAR T-cell infusion without consolidation therapies will be measured by complete blood count and flow cytometry.	from enrollment to the end of treatment at 15 years
Primary	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.	2-year EFS rate
Secondary	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.	3 months (± 1 week) ORR
Secondary	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.	from enrollment to the end of treatment at 15 years
Secondary	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.	from enrollment to the end of treatment at 15 years
Secondary	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.	from enrollment to the end of treatment at 2 years
Secondary	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.	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Secondary	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.	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Secondary	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).	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Secondary	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).	from CD19 CAR T-cell infusion to the end of treatment at 15 years
Secondary	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.	from enrollment to the end of treatment at 15 years