Bispecific CD19/CD22 CAR-T for Treatment of Children and Young Adults With r/r B-ALL

February 21, 2023 updated by: Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Safety and Efficiency of Anti-CD19/CD22 Tandem Fully Human Chimeric Antigen Receptor (CAR)-Transduced T-cell Therapy for Pediatric and Young Adult Patients With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: a Single Centre, Non-randomised, Open Label Phase I-II Clinical Trial of Automatically Produced Cell Therapy Product MB-CAR-T19-22 Using CliniMACS Prodigy

The purpose of this study is to evaluate the safety and efficiency of autologous CD19/CD22 CAR-T lymphocytes in a cohort of pediatric and young adult patients with relapsed /refractory B-lineage acute lymphoblastic leukemia

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The main objectives of the study are:

  • To investigate the incidence of adverse events of grade 3-5 within after CD19/CD22 CAR lymphocyte infusion by day 28,
  • To evaluate the incidence of complete remission and MRD-negative CR by day 28
  • To evaluate the long-term effectiveness of CD19/CD22 CAR-T therapy (cumulative incidence of relapse, event-free survival, overall survival) at 1, 2, and 5 years after infusion.
  • To evaluate the persistence of CD19/CD22 CAR-T cells and duration of B-cell aplasia (<1% B-cells in the blood) and hypogammaglobulinemia In order to prevent the development of CRS, all patients will receive an infusion of tocilizumab at 8 mg/kg body weight on day 0 before CAR-T cells infusion.

Step-down and step-up dosing will be used to adapt the trial to the scenario of excess toxicity and/or suboptimal effect. Reevaluation of dosing will be done for each cohort separately after the enrollment 5th study subject reaches day 28 or earlier if the threshold for excess toxicity or suboptimal effect is achieved.

Based on interim analysis in March 2021 after the enrollment 5th study subject reaches day 28 study population will be divided into three cohorts:

  1. CD19-positive (both CD19 and CD22 expressed on over 50% of leukemia cells), low and high disease burden.
  2. CD19-negative (CD22 expressed on over 50% of leukemia cells) low and high disease burden;
  3. Allogeneic HSCT+ allogeneic CAR-T cohort

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
50

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Russian Federation
      • Moscow, Russian Federation, 117198
        • Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

3 months to 25 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent
  • CD19 or CD22 expression must be detected on greater than 50% of leukemic cells by flow cytometry
  • Presence of a measurable mass of tumor cells in the bone marrow or extramedullary sites at the time of patient's inclusion in the study

  • Patients with relapsed or refractory CD19 and CD22-expressing B-cell ALL:

    • Induction failure
    • MRD ≥ 0,1% after 2nd chemotherapy course for high-risk group patients.
    • First bone marrow or combined relapse of acute lymphoblastic leukemia, no CR or MRD ≥ 0,1% after 1-course 2nd line therapy
    • Second and further relapse of ALL
    • Relapse or MRD ≥ 0,1% of ALL after hematopoietic stem cell transplant (> 60 days post alloHSCT)o There must be no available alternative approved curative therapies
  • Patient Clinical Performance Status: Karnofsky >50% or Lansky >50%
  • Patient Life Expectancy > 4 weeks
  • Patients recovered from acute toxic effects of prior chemotherapy, immune- or radiotherapy
  • Patient absolute blood naïve (CD45RA+) T-lymphocyte count ≥ 50/mm3
  • Patient cardiac function left ventricular ejection fraction greater than or equal to 40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO.
  • Patients who agree to long-term follow up for up to 5 years (if received CD19/CD22 CAR-T cell infusion)
  • March 2021 amendment: Healthy HLA-matched related or haploidentical donor (only for HSCT cohort)

Exclusion Criteria:

  • <50% expression of both CD19 and CD22 on the leukemic population
  • Active (detectable viremia) hepatitis B, C or HIV infection
  • Oxygen saturation ≤ 90%
  • Bilirubin >3x upper norma limit
  • Creatinine >3x upper norma limit
  • Active acute GVHD overall grade ≥2 (Seattle criteria)
  • Moderate/severe chronic GVHD (NIH consensus) requiring systemic steroids
  • Clinical signs of grade > 3 CNS disorders (seizure disorder, paresis, aphasia, cerebrovascular, ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
  • Pregnant or lactating women.
  • Active (unresolved) severe infection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: intervention/treatment

Intervention:

  1. Patient (cohort 1 and 2) or donor (cohort 3) leukapheresis

  2. Drug therapy:

    • Fludarabine 120 mg/m2
    • Cyclophosphamide 750 mg/m2
    • Etoposide 450 mg/m2
    • Cytarabine 900 mg/m2
    • Dexamethasone 30 mg/m2
    • Tocilizumab 8 mg/kg BW
  3. Biological:

Cohort 1 and 2: autologous CD19/CD22 CAR-T lymphocytes, dose 0.15 - 1.5х106/kg

Cohort 3: allogeneic CD19/CD22 CAR-T lymphocytes, dose 0.1х106/kg + allogeneic HSCT from a haploidentical or matched related donor
Drug: CD19/CD22 CAR-T

The treatment plan will be based on stratification by the initial leukemia burden.

Patients with "low disease burden" will receive a lymphodepletion chemotherapy of fludarabine (total dose 120mg/m2) and cyclophosphamide (total dose 750mg/m2) over 5 days.

Patients will "high disease burden" will receive a lymphodepletion chemotherapy of fludarabine (total dose 120 mg/m2), cyclophosphamide (total dose 750 mg/m2), cytarabine (total dose 900 mg/m2), etoposide (total dose 450 mg/m2), dexamethasone (total dose 30 mg/m2) over 5 days.

Based on interim analysis the following dosing approach will be implemented starting April 2021:

Cohort 1: CD19+ disease, low and high burden: 1st dose - 150k/kg, 2nd dose - 850k/kg Cohort 2: CD19- disease, low and high burden: 1st dose - 500k/kg, 2nd dose - 500k/kg Cohort 3: HSCT+CAR-T: 100k/kg

Other Names:
  • Dexamethasone
  • Cytarabine
  • Cyclophosphamide
  • Etoposide
  • Fludarabine
  • Tocilizumab
  • Allogeneic HSCT

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
incidence of grade 3-5 SAE
Time Frame: 1 month

Safety:

Toxicity evaluation following CD19/CD22 CAR T-cell infusion:

- incidence of grade 3-5 SAE (according CTCAE v.5.0)
1 month
incidence of grade 3-5 Severe Cytokine Release Syndrome
Time Frame: 1 month

Safety:

Toxicity evaluation following CD19/CD22 CAR T-cell infusion:

- incidence of grade 3-5 Severe Cytokine Release Syndrome (according ASTCT consensus)
1 month
incidence of grade 3-5 ICANS
Time Frame: 1 month

Safety:

Toxicity evaluation following CD19/CD22 CAR T-cell infusion:

- incidence of grade 3-5 ICANS (according to ASTCT consensus)
1 month
Rate of complete remission
Time Frame: 1 month

Efficacy:

- Rate of complete remission among all enrolled patients (Intent-to-Treat population)
1 month
Rate of MRD-negative remission
Time Frame: 1 month

Efficacy:

- Rate of MRD-negative remission among all patients (Intent-to-treat population)
1 month
March 2021 amendment: incidence of graft failure before day 100 (only for HSCT cohort)
Time Frame: 100 days
Safety:
100 days
March 2021 amendment: incidence of aGVHD grade 2-4 (only for HSCT cohort)
Time Frame: 100 days
Safety:
100 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Duration of MRD-negative remission
Time Frame: 2 years
Efficacy:
2 years
Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)
Time Frame: 2 years
Efficacy:
2 years
Duration of B-cell aplasia and hypogammaglobulinemia
Time Frame: 2 years
Efficacy:
2 years
Overall survival
Time Frame: 5 years
Efficacy:
5 years
Safety and adverse effects long-term
Time Frame: 5 years
Safety:
5 years
March 2021 amendment: Incidence of chronic GVHD (only for HSCT cohort)
Time Frame: 5 years
Safety:
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Michael Maschan, National Research Center for Pediatric Hematology , Moscow, Russian Federation

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 27, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 13, 2022

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 13, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 31, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 31, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 5, 2020

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 22, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 21, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NCPHOI-2020-07

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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