Clinical Trials /

Study of the Tocilizumab Optimization Timing for CART19 Associated Cytokine Release Syndrome

NCT02906371

Description:

This is a two cohort, open-label, pilot study to describe the efficacy of administration timing of tocilizumab on CART19 (CTL019) associated cytokine release syndrome safety events in pediatric patients with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia with high versus low pre-infusion tumor burden following redirected autologous T cells transduced with the anti-CD19 lentiviral vector (CART19/CTL019).

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

N/A

Trial Eligibility

Document

Title

  • Brief Title:Study of the Tocilizumab Optimization Timing for CART19 Associated Cytokine Release Syndrome
  • Official Title:A Two Cohort Pilot Study of the Tocilizumab Optimization Timing for CART19 Associated Cytokine Release Syndrome (CRS) Management in Pediatric Patients With CD19 Expressing Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 16CT022
  • NCT ID: NCT02906371

Trial Conditions

  • Lymphoblastic Leukemia, Acute, Childhood

Trial Interventions

DrugSynonymsArms
Tocilizumabhigh tumor burdenTocilizumab high tumor burden
Tocilizumablow tumor burdenTocilizumab low tumor burden

Trial Purpose

This is a two cohort, open-label, pilot study to describe the efficacy of administration timing of tocilizumab on CART19 (CTL019) associated cytokine release syndrome safety events in pediatric patients with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia with high versus low pre-infusion tumor burden following redirected autologous T cells transduced with the anti-CD19 lentiviral vector (CART19/CTL019).

Detailed Description

The duration of active protocol intervention is approximately 12-15 months from the screening visit. The protocol will require approximately 12-18 months to complete enrollment.Approximately 39 enrolled patients to reach at least 35 infused patients, with the ultimate goal of 15 patients in the high tumor burden cohort (Cohort A). Inclusion criteria are designed to include pediatric patients aged 1-24 years with CD19 expressing relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).Tocilizumab will be given once to high disease burden patients, and then the patients will be managed for CRS as per the standard algorithm (including subsequent tocilizumab, if needed).

Two cohorts are defined based upon pre-infusion high versus low tumor burden; with the high tumor burden cohort (high risk of severe CRS) to receive earlier administration of tocilizumab for CRS management and the low tumor burden cohort (low risk of severe CRS) to receive standard timing of tocilizumab for CRS

Trial Arms

NameTypeDescriptionInterventions
Tocilizumab high tumor burdenActive ComparatorThis is a two cohort, open-label, pilot study to describe the efficacy of administration timing of tocilizumab on CART19 (CTL019) associated CRS safety events in pediatric patients with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia with high pre-infusion tumor burden following redirected autologous T cells transduced with the anti-CD19 lentiviral vector (CART19/CTL019).
  • Tocilizumab
    Tocilizumab low tumor burdenActive ComparatorThis is a two cohort, open-label, pilot study to describe the efficacy of administration timing of tocilizumab on CART19 (CTL019) associated CRS safety events in pediatric patients with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia with low pre-infusion tumor burden following redirected autologous T cells transduced with the anti-CD19 lentiviral vector (CART19/CTL019).
      • Tocilizumab

      Eligibility Criteria

      Inclusion Criteria:

      1. Signed informed consent form must be obtained prior to any study procedure. Labs, marrows or other procedures obtained during routine clinical care may be used for eligibility if obtained within the protocol required windows.

      2. Relapsed or refractory B-cell ALL/lymphoblastic lymphoma:

      1. 2nd or greater relapse (marrow or CNS) OR

      2. Any relapse after allogeneic hematopoietic stem cell (SCT) transplant and ≥ 6 months from stem cell transplantation at infusion OR

      3. Any relapse after CAR-modified T cell therapy OR

      4. Refractory disease defined as having not achieved an MRD-negative CR after > 2 chemotherapy regimens/cycles (1 cycle for relapsed patients) OR

      5. Patients with Ph+ ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR

      6. Ineligible for allogeneic SCT because of:

      - Comorbid disease

      - Other contraindications to allogeneic SCT conditioning regimen

      - Lack of suitable donor

      - Prior SCT

      - Declines allogeneic SCT as the therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a bone marrow transplant (BMT) physician not part of the study team

      7. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy (at infusion, must meet criteria in Section 5.3)

      3. Documentation of CD19 tumor expression in bone marrow or peripheral blood by flow cytometry at relapse (or a recent marrow in the case of refractory disease). If the patient has received CD19-directed therapy (i.e. blinatumomab), then the marrow should be obtained after this therapy to show CD19 expression.

      4. Adequate organ function defined as:

      1. A serum creatinine based on age/gender as follows:

      Maximum Serum Creatinine (mg/dL)

      Age Male Female

      - 1 to < 2 years 0.6 0.6

      - 2 to < 6 years 0.8 0.8

      - 6 to < 10 years 1.0 1.0

      - 10 to < 13 years 1.2 1.2

      - 13 to < 16 years 1.5 1.4

      - ≥ 16 years 1.7 1.4

      2. ALT< 500 U/L

      3. Bilirubin <2.0 mg/dl

      4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, pulse oximetry > 92% on room air; DLCO > 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator

      5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist.

      5. Evidence of disease by standard morphologic or MRD criteria. A clinical marrow showing disease may be performed at enrollment or within 12 weeks of enrollment.

      6. Age 1-24 years.

      7. Adequate performance status (Lansky or Karnofsky score ≥50).

      8. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.

      Exclusion Criteria:

      1. Active hepatitis B or active hepatitis C.

      2. HIV Infection.

      3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.

      4. Concurrent use of systemic steroids or immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary. For additional details regarding the use of steroids and immunosuppressant medication, please see Section 5.6.

      5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.

      6. Pregnant or nursing (lactating) women.

      7. Receipt of a prior investigational study agent within 4 weeks prior to screening visit.

      - Note- patients who have received anti-CD19 CART cells on a study where cell infusion occurred greater than 4 weeks before the screening visit are NOT excluded.

      Maximum Eligible Age:24 Years
      Minimum Eligible Age:1 Year
      Eligible Gender:Both
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:the frequency of grade 4 CRS
      Time Frame:from day 1 to 1 year
      Safety Issue:Yes
      Description:Frequency of CRS grade 4

      Secondary Outcome Measures

      Measure:tumor response
      Time Frame:day 28
      Safety Issue:No
      Description:Frequency of CR with minimal residual disease negative bone marrow at day 28 and duration of remission

      Trial Keywords