- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04499573
Bispecific CD19/CD22 CAR-T for Treatment of Children and Young Adults With r/r B-ALL
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
Study Overview
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:
- CD19-positive (both CD19 and CD22 expressed on over 50% of leukemia cells), low and high disease burden.
- CD19-negative (CD22 expressed on over 50% of leukemia cells) low and high disease burden;
- Allogeneic HSCT+ allogeneic CAR-T cohort
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Olga Molostova
- Phone Number: 7535 +7(495)2876570
- Email: Olga.molostova@gmail.com
Study Locations
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Moscow, Russian Federation, 117198
- Federal Research Institute of Pediatric Hematology, Oncology and Immunology
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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 |
Intervention / Treatment |
---|---|
Experimental: intervention/treatment
Intervention:
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 |
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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
incidence of grade 3-5 SAE
Time Frame: 1 month
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Safety: Toxicity evaluation following CD19/CD22 CAR T-cell infusion: - incidence of grade 3-5 SAE (according CTCAE v.5.0) |
1 month
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incidence of grade 3-5 Severe Cytokine Release Syndrome
Time Frame: 1 month
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Safety: Toxicity evaluation following CD19/CD22 CAR T-cell infusion: - incidence of grade 3-5 Severe Cytokine Release Syndrome (according ASTCT consensus) |
1 month
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incidence of grade 3-5 ICANS
Time Frame: 1 month
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Safety: Toxicity evaluation following CD19/CD22 CAR T-cell infusion: - incidence of grade 3-5 ICANS (according to ASTCT consensus) |
1 month
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Rate of complete remission
Time Frame: 1 month
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Efficacy: - Rate of complete remission among all enrolled patients (Intent-to-Treat population) |
1 month
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Rate of MRD-negative remission
Time Frame: 1 month
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Efficacy: - Rate of MRD-negative remission among all patients (Intent-to-treat population) |
1 month
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March 2021 amendment: incidence of graft failure before day 100 (only for HSCT cohort)
Time Frame: 100 days
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Safety:
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100 days
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March 2021 amendment: incidence of aGVHD grade 2-4 (only for HSCT cohort)
Time Frame: 100 days
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Safety:
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100 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Duration of MRD-negative remission
Time Frame: 2 years
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Efficacy:
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2 years
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Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)
Time Frame: 2 years
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Efficacy:
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2 years
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Duration of B-cell aplasia and hypogammaglobulinemia
Time Frame: 2 years
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Efficacy:
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2 years
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Overall survival
Time Frame: 5 years
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Efficacy:
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5 years
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Safety and adverse effects long-term
Time Frame: 5 years
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Safety:
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5 years
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March 2021 amendment: Incidence of chronic GVHD (only for HSCT cohort)
Time Frame: 5 years
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Safety:
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5 years
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Collaborators and Investigators
Investigators
- Principal Investigator: Michael Maschan, National Research Center for Pediatric Hematology , Moscow, Russian Federation
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Dexamethasone
- Cyclophosphamide
- Etoposide
- Fludarabine
- Cytarabine
Other Study ID Numbers
- NCPHOI-2020-07
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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