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

Official title

Safety, Tolerability and Pharmacokinetics of Donor-derived CD19 CAR Therapy Bridged Allogeneic Haematopoietic Stem Cell Transplantation and Sequential Donor-derived CD22 CAR Therapy in Refractory or Relapsed B Cell Acute Lymphoblastic Leukemia: a Clinical Trial

Overview

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.

Interventions

• Drug Donor-derived CD19 CAR Therapy Bridged Allo-HSCT and Sequential Donor-derived CD22 CAR Therapy
  Peripheral blood mononuclear cells for the production of CD19 CAR T cells and CD22 CAR T cells are collected from donors and haematopoietic stem cells are collected from donors.

Primary outcome measures

• Dose-limiting toxicity (DLT) [Time frame: Within 43 days of donor-derived CD19 CAR T-cell infusion]
• Adverse events (AEs) [Time frame: Within 120 days of donor-derived CD19 CAR T-cell infusion]

Secondary outcome measures (8)

• Long-term Adverse events (AEs) [Time frame: From 120 days to 2 years after donor-derived CD19 CAR T-cell infusion]
• Objective response rate(ORR) [Time frame: day 30, day 45, day 90]
• Duration of response (DOR) [Time frame: Up to 2 years]
• Event-free survival (EFS) [Time frame: Up to 2 years]
• Overall survival (OS) [Time frame: Up to 2 years]
• The persistence of CD19/CD22 CAR T cells. [Time frame: Up to 2 years]
• The Maximum concentration (Cmax) of CD19/CD22 CAR T cells. [Time frame: Up to 2 years]
• The time to maximum plasma concentration (Tmax) of CD19/CD22 CAR T cells. [Time frame: Up to 2 years]

Eligibility criteria

Inclusion criteria

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

• 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);
• Peripheral blood tumour burden ≥60% or severe peripheral blood cytopenia, unsuitable/unable to collect autologous lymphocytes;
• 1 to 18 years old;
• Patient's expected survival time ≥ 60 days;
• Physical status: ECOG score 0-2;
• Availability of allogeneic donors (HLA-identical or HLA-haploidentical) DSA-negative for collection of peripheral blood mononuclear cells and peripheral blood stem cells;
• 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.

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

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Beijing GoBroad Hospital — Beijing

Identifiers

NCT: NCT06326008 · BJGBYY-IIT-LCYJ-2023-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗