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
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Incidence of grade 3-5 SAE occurring within 30 days of CD19CAR T-cell infusion
Study Overview
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
Detailed Description
The main objectives of the study are:
- 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
- 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.
- 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 3 Months to 25 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
- •<30% expression of CD19 on the leukemic population
- •Active hepatitis B, C or HIV infection
- •Oxygen saturation < or = 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 severe infection
Arms & Interventions
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.
Intervention: Chimeric Antigen Receptor T-Cell Therapy (Biological)
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.
Intervention: Fludarabine (Drug)
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.
Intervention: Cyclophosphamide (Drug)
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.
Intervention: Tocilizumab (Drug)
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.
Intervention: Cytarabine (Drug)
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.
Intervention: Etoposide (Drug)
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.
Intervention: Dexamethasone (Drug)
Outcomes
Primary Outcomes
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
Proportion of patients in MRD-negative remission
Time Frame: 1 month
Proportion of patients in MRD-negative remission among all enrolled patients
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
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
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
Secondary Outcomes
- Duration of B-cell aplasia(5 years)
- Overall survival(5 years)
- Duration of MRD-negative remission(2 years)
- Persistence/frequency of CD19 CAR T lymphocytes in peripheral (FC+qPCR)(2 years)