Safety, Tolerability, and Pharmacokinetics of Donor-derived CD19 CAR Therapy Bridged Allo-HSCT and Sequential Donor-derived CD22 CAR Therapy for r/r B-ALL: a Clinical Trial

Phase 1

Not yet recruiting

• Conditions: B-cell Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, in Relapse
• Interventions: Drug: Donor-derived CD19 CAR Therapy Bridged Allo-HSCT and Sequential Donor-derived CD22 CAR Therapy

• Registration Number: NCT06326008
• Lead Sponsor: Beijing GoBroad Hospital

Brief Summary

This is an investigator-initiated, single-arm, open-label, non-randomised phase I clinical study. The objective of this trial is to evaluate the safety, tolerability and pharmacokinetics of donor-derived CD19 CAR Therapy bridged Allo-HSCT and sequential donor-derived CD22 CAR Therapy for r/r B-ALL and to explore the efficacy of this therapy preliminarily. The primary endpoints are incidence and type of dose-limiting toxicity (DLT) within 28 days (i.e., 43 days after donor-derived CD19 CAR T-cell infusion) after donor-derived CD19 CAR T-cell therapy bridged allogeneic haematopoietic stem cell transplantation; total number, incidence and severity of adverse events from donor-derived CD19 CAR T cell infusion back to 30 days after donor-derived CD22 CAR T cell infusion (i.e., within 120 days of donor-derived CD19 CAR T cell infusion). The secondary endpoints are total number, incidence and severity of adverse events from 120 days to 2 years after donor-derived CD19 CAR T-cell infusion; ORR(CR+CRi) on days 45, 90, 120; duration of response(DOR), event-free survival(EFS), overall survival(OS); pharmacokinetics characteristics. The trial plan to enroll 3\~12 cases in dose escalation phase and 36 cases in dose expansion phase.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-03-10
• Study First Submitted QC: 2024-03-15
• Study First Posted: 2024-03-22
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-24
• Last Update Posted: 2024-10-28
• Study Start: 2024-12-15
• Primary Completion: 2026-06-15
• Study Completion: 2026-12-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

• Patients will be enrolled only if they meet all the inclusion criteria.

1. Patients with relapsed or refractory CD19+/CD22+ (FCM >95%) B-cell acute lymphoblastic leukaemia who have progressed despite or are intolerant to all standard therapies, including, but not limited to, immunotherapies such as Blinatumomab (BITE), Tyrosine kinase inhibitors (TKI), CAR T-cell therapy, etc.; Currently available therapies have a limited prognosis and there are no available curative treatment options (e.g., HSCT or chemotherapy);
2. Peripheral blood tumour burden ≥60% or severe peripheral blood cytopenia, unsuitable/unable to collect autologous lymphocytes;
3. 1 to 18 years old;
4. Patient's expected survival time ≥ 60 days;
5. Physical status: ECOG score 0-2;
6. Availability of allogeneic donors (HLA-identical or HLA-haploidentical) DSA-negative for collection of peripheral blood mononuclear cells and peripheral blood stem cells;
7. Sign an informed consent form during the screening period. Pediatric patients under 8~18 years of age need to have sufficient awareness to voluntarily sign an informed consent form, and their legal representatives (guardians) also need to voluntarily sign an informed consent form; pediatric patients aged 1~7 years can only be recruited after their legal guardians have voluntarily signed an informed consent form.

Exclusion Criteria

• Patients who meet any of the following criteria are not eligible for enrolment.

  1. Patients who have received previous haematopoietic stem cell transplantation (including peripheral blood haematopoietic stem cell transplantation and bone marrow haematopoietic stem cell transplantation);
  2. Intracranial hypertension or cerebral impaired consciousness;
  3. Symptomatic heart failure or severe cardiac arrhythmia;
  4. Symptoms of severe respiratory failure;
  5. With other types of malignant tumours;
  6. Diffuse intravascular coagulation;
  7. Serum creatinine and/or urea nitrogen ≥ 1.5 times the normal value;
  8. Suffering from sepsis or other uncontrollable infections;
  9. Suffering from uncontrollable diabetes mellitus;
  10. Severe mental disorders;
  11. Have significant intracranial lesions on cranial MRI (excluding intracranial masses caused by central nervous system leukaemia);
  12. Have organ transplant history;
  13. Female patients (patients of childbearing potential) with positive blood HCG test;
  14. Hepatitis (including Hepatitis B and Hepatitis C) and positive screening for AIDS and syphilis;
  15. No allogeneic donor suitable for collection of peripheral blood lymphocytes and haematopoietic stem cells.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm-1	Donor-derived CD19 CAR Therapy Bridged Allo-HSCT and Sequential Donor-derived CD22 CAR Therapy	Participants receive donor-derived CD19 CAR therapy bridged Allo-HSCT and sequential donor-derived CD22 CAR therapy

Primary Outcome Measures

Name	Time	Method
Adverse events (AEs)	Within 120 days of donor-derived CD19 CAR T-cell infusion	Total number, incidence and severity of adverse events (AEs) from the time of donor-derived CD19 CAR T cell infusion back to 30 days after donor-derived CD22 CAR T cell infusion (i.e., within 120 days of donor-derived CD19 CAR T-cell infusion) will be recorded.
Dose-limiting toxicity (DLT)	Within 43 days of donor-derived CD19 CAR T-cell infusion	Incidence and type of dose-limiting toxicity (DLT) within 28 days (i.e., 43 days after donor-derived CD19 CAR T-cell infusion) after donor-derived CD19 CAR T-cell therapy bridging allogeneic haematopoietic stem cell transplantation will be recorded.

Secondary Outcome Measures

Name	Time	Method
Long-term Adverse events (AEs)	From 120 days to 2 years after donor-derived CD19 CAR T-cell infusion	Total number, incidence and severity of AEs from 120 days to 2 years after donor-derived CD19 CAR T-cell infusion will be recorded.
Objective response rate(ORR)	day 30, day 45, day 90	Objective response rate (ORR) at day 30, day 45, day 90 as determined by the National Comprehensive Cancer Network (NCCN) GuidelinesVersion 3.2023 of Acute Lymphoblastic Leukemia.
Duration of response (DOR)	Up to 2 years	DOR is defined as the date when CR or CRi response criteria are first met to the date of relapse or death caused by ALL in the absence of documented relapse.
Event-free survival (EFS)	Up to 2 years	EFS is defined as the time from donor-derived CD19 CAR T-cell infusion to the occurrence of any event, which includes disease progression, discontinuation of therapy for any reason, or death.
The Maximum concentration (Cmax) of CD19/CD22 CAR T cells.	Up to 2 years	The Maximum concentration (Cmax) of CD19/CD22 CAR T cells will be recorded.
The persistence of CD19/CD22 CAR T cells.	Up to 2 years	The persistence of CD19/CD22 CAR T cells in cerebral spinal fluid (CSF) and peripheral blood will be detected by flowcytometry and qPCR after CD19/CD22 CAR T cells infusion.
Overall survival (OS)	Up to 2 years	OS is defined as the time from the infusion of donor-derived CD19 CAR T cells until death due to any cause.
The time to maximum plasma concentration (Tmax) of CD19/CD22 CAR T cells.	Up to 2 years	The time to maximum plasma concentration (Tmax) of CD19/CD22 CAR T cells will be recorded.