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

NCT04499573 | Active Not Recruiting Phase 1

• 1 other identifier: NCPHOI-2020-07
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

B-ALL

Keywords

B-ALL; acute lymphoblastic leukemia; CAR-T

Outcome Measures

Primary Outcomes (7)

• incidence of grade 3-5 SAE

  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

  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

  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

  Efficacy: \- Rate of complete remission among all enrolled patients (Intent-to-Treat population)

  1 month

• Rate of MRD-negative remission

  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)

  Safety:

  100 days

• March 2021 amendment: incidence of aGVHD grade 2-4 (only for HSCT cohort)

  Safety:

  100 days

Secondary Outcomes (6)

• Duration of MRD-negative remission

  2 years

• Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)

  2 years

• Duration of B-cell aplasia and hypogammaglobulinemia

  2 years

• Overall survival

  5 years

• Safety and adverse effects long-term

  5 years

Study Arms (1)

intervention/treatment

EXPERIMENTAL

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

Interventions

CD19/CD22 CAR-T DRUG

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

Also known as: Fludarabine, Cyclophosphamide, Cytarabine, Etoposide, Dexamethasone, Tocilizumab, Allogeneic HSCT

intervention/treatment

Eligibility Criteria

• Age: 3 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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
• 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)

You may not qualify if:

• \<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

Sponsors & Collaborators

• Federal Research Institute of Pediatric Hematology, Oncology and Immunology: lead

Study Sites (1)

Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Moscow, 117198, Russia

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

fludarabine; Cyclophosphamide; Cytarabine; Etoposide; Dexamethasone; tocilizumab

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated

Study Officials

• Michael Maschan

  National Research Center for Pediatric Hematology , Moscow, Russian Federation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2020
• First Posted: August 5, 2020
• Study Start: July 27, 2020
• Primary Completion: March 13, 2022
• Study Completion (Estimated): March 13, 2027
• Last Updated: February 22, 2023

Record last verified: 2023-02

Locations

RU (1)