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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03467256
Recruitment Status : Active, not recruiting
First Posted : March 15, 2018
Last Update Posted : February 24, 2023
Sponsor:
Information provided by (Responsible Party):
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

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

Condition or disease Intervention/treatment Phase
B-cell Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia, Pediatric Biological: Chimeric Antigen Receptor T-Cell Therapy Drug: Fludarabine Drug: Cyclophosphamide Drug: Tocilizumab Drug: Cytarabine Drug: Etoposide Drug: Dexamethasone Phase 1 Phase 2

Detailed Description:

The main objectives of the study are:

  1. To investigate the safety of auto-CD19 CAR T-cells therapy among children and young adults with refractory/relapsed B-cell ALL on the basis of prospective evaluation of adverse affects frequency and severity according to CTCAE v.4
  2. To study the efficacy of auto-CD19 CAR T-cells therapy among children and young adults with refractory/relapsed B-cell ALL on the basis of proportion of patients in haematological and molecular remission at 28 days after infusion.
  3. To evaluate long-term efficacy of auto-CD19 CAR T-cells therapy among children and young adults with refractory/relapsed B-cell ALL on the basis of overall and event-free survival at 1 and 3 years after infusion.

The novelty of this study will be cytokine release syndrome prophylaxis by tocilizumab Patients will receive fludarabine 120 mg/m2 (totally) intravenously (IV) over 30 minutes on days -5 to -2 and cyclophosphamide 750 mg/m2 IV over 60 minutes on day -2. One hour prior to infusion of CAR T-cells patients will receive tocilizumab IV 8 mg/kg (max 800 mg) over 1 hour. Patients then receive CD19-CAR T cells IV over 20-30 minutes on day 0.

This is a dose-escalation study of CD19-CAR T cells. Dose escalation consistently:

  • Level 1 5х105/kg CD19 CAR-T lymphocytes
  • Level 2 1х106/kg CD19 CAR-T lymphocytes
  • Level 3 3х106/kg CD19 CAR-T lymphocytes
  • Level 0 1х105/kg CD19 CAR-T lymphocytes (in case of dose-limiting toxicity at dose Level 1) In case of severe side affects next dose will be reduced to the previous lower dose.

Based on interim analysis the following dosing approach based on stratification by the initial leukemia burden will be implemented starting November 2019:

• Patients with low disease burden (<15% blast cells in BM) will receive a lymphodepletion chemotherapy of fludarabine IV (total dose 120mg/m2) and cyclophosphamide IV (total dose 750mg/m2) over 5 days.

CD19 CAR-T cells will be infused IV in dose 1x106/kg on day 0.

• Patients will high disease burden (>15% blast cells in BM) will receive a lymphodepletion chemotherapy of fludarabine IV (total dose 120 mg/m2), cyclophosphamide IV (total dose 750 mg/m2), cytarabine IV (total dose 900 mg/m2), etoposide IV (total dose 450 mg/m2), dexamethasone IV (total dose 30 mg/m2) over 5 days.

CD19 CAR-T cells 1st dose will be infused IV on day 0 - 0,1x106/kg, 2nd dose will be infused IV between day 7 and 14 - 0,9x106/kg.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Arm Phase I/II Study Evaluating the Safety and Clinical Efficacy Of the 2-nd Generation CD19 Autologous CAR T Cells on the CliniMACS Prodigy Automated Manufacturing Platform in Treatment of Paediatric And Young Adult Patients With Relapsed/Refractory B-lineage Acute Lymphoblastic Leukemia
Actual Study Start Date : May 14, 2018
Actual Primary Completion Date : October 15, 2020
Estimated Study Completion Date : October 15, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: experimental
Patients will receive lymphodepleting chemotherapy, one hour prior to infusion of CAR T-cells patients will receive tocilizumab IV 8 mg/kg (max 800 mg) over 1 hour. Patients then receive CD19-CAR T cells IV on day 0.
 Biological: Chimeric Antigen Receptor T-Cell Therapy
anti-CD19 chimeric antigen receptor - transduced T-cell given IV

Drug: Fludarabine
given IV

Drug: Cyclophosphamide
given IV

Drug: Tocilizumab
given IV

Drug: Cytarabine
given IV

Drug: Etoposide
given IV

Drug: Dexamethasone
given IV


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of grade 3-5 SAE occurring within 30 days of CD19CAR T-cell infusion [ Time Frame: 1 month ]
    incidence of grade 3-5 SAE according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 occurring within 30 days of CD19CAR T-cell infusion

  2. Incidence of grade 3-4 Severe Cytokine Release Syndrome following CD19 CAR T-cell infusion [ Time Frame: 1 month ]
    incidence of grade 3-4 Severe Cytokine Release Syndrome

  3. Incidence of grade 3-5 neurotoxicity occurring within 30 days of CD19 CAR T-cell infusion [ Time Frame: 1 month ]
    incidence of grade 3-5 neurotoxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 occurring within 30 days of CD19 CAR T-cell infusion

  4. Proportion of patients in MRD-negative remission [ Time Frame: 1 month ]
    Proportion of patients in MRD-negative remission among all enrolled patients

  5. Proportion of patients in hematologic remission [ Time Frame: 1 months ]
    Proportion of patients in hematologic remission among all patients with morphological disease (NO CR) at enrollment


Secondary Outcome Measures :
  1. Duration of MRD-negative remission [ Time Frame: 2 years ]
    Duration of MRD-negative remission

  2. Persistence/frequency of CD19 CAR T lymphocytes in peripheral (FC+qPCR) [ Time Frame: 2 years ]
    Persistence/frequency of CD19 CAR T lymphocytes in peripheral (FC+qPCR)

  3. Duration of B-cell aplasia [ Time Frame: 5 years ]
    Duration of B-cell aplasia and hypogammaglobulinemia, time 0 - day of CD19-CAR T cells infusion

  4. Overall survival [ Time Frame: 5 years ]
    the probability of survival, time 0 - day of CD19-CAR T cells infusion


Eligibility Criteria
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Ages Eligible for Study:   3 Months to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent

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

    • Induction failure, no CR after course 2 or MRD>0,1% after 3 courses of high-risk protocol
    • early bone marrow or combined relapse of acute lymphoblastic leukaemia, no CR or MRD>0,1% after 1 course 2-nd line therapy
    • ALL post ≥ 2nd relapse, no CR or MRD>0,1% after 1 course 2-nd line therapy
    • Relapse or MRD >0,1% of ALL after stem cell transplant (> 60 days post alloHSCT)
    • Late bone marrow or combined relapse of acute lymphoblastic leukaemia, no CR or MRD>0,1% after 2nd course of 2-nd line therapy
  • There must be no available alternative curative therapies
  • CD19 expression must be detected on greater than 30% by flow cytometry
  • Patients must have measurable or evaluable disease at the time of enrolment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
  • Patient Clinical Performance Status: Karnofsky >50% or Lansky >50%
  • Patient Life Expectancy > 8 weeks
  • Patients recovered from acute toxic effects of all prior chemotherapy, immuno- or radiotherapy
  • Patient absolute lymphocyte N > or =100/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 CAR-T cell infusion)

Exclusion Criteria:

  1. <30% expression of CD19 on the leukemic population
  2. Active hepatitis B, C or HIV infection
  3. Oxygen saturation < or = 90%
  4. Bilirubin >3x upper norma limit
  5. Creatinine >3x upper norma limit
  6. Active acute GVHD overall grade ≥2 (Seattle criteria)
  7. Moderate/severe chronic GVHD (NIH consensus) requiring systemic steroids
  8. 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)
  9. Pregnant or lactating women.
  10. Active severe infection
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03467256


Locations
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Russian Federation
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Moscow, Russian Federation, 117198
Sponsors and Collaborators
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
ClinicalTrials.gov Identifier: NCT03467256    
Other Study ID Numbers: NCPHOI-2018-01
First Posted: March 15, 2018    Key Record Dates
Last Update Posted: February 24, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Dexamethasone
Cyclophosphamide
Fludarabine
Etoposide
Immunosuppressive Agents
 Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones