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:

Completed

Phase:

Phase 1

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, 825445
  • NCT ID: NCT02906371

Conditions

  • Lymphoblastic Leukemia, Acute, Childhood

Interventions

DrugSynonymsArms
Tocilizumabhigh tumor burdenTocilizumab high tumor burden
Tocilizumablow tumor burdenTocilizumab low tumor burden
CART 19Tocilizumab high tumor burden

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
  • CART 19
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
  • CART 19

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:

               1. 2nd or greater marrow relapse OR

               2. CNS relapse OR

               3. Any relapse after allogeneic hematopoietic stem cell (SCT) transplant and ≥ 4
                  months from SCT at enrollment OR

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

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

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

               7. 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

               8. Patients with B lymphoblastic lymphoma will be eligible if they meet one of the
                  above criteria OR:

                    -  2nd or greater relapse OR

                    -  Refractory disease defined as having not achieved CR with frontline therapy
                       or after 1 cycle of reinduction therapy for relapsed patients

               9. Patients with prior or current history of 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, peripheral blood, CSF, or tumor
             tissue by flow cytometry at relapse (or a recent sample in the case of refractory
             disease). If the patient has received CD19-directed therapy (i.e. blinatumomab), then
             the flow cytometry 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 or
             tissue biopsy showing disease may be performed at enrollment or within 12 weeks of
             enrollment. Presence of marrow disease not required for CNS disease or lymphoblastic
             lymphoma patients.

          6. Age 1-29 years. Patients ages 24-29 years are eligible if their original leukemia
             diagnosis was prior to age 21.

          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.

        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. 8. Uncontrolled active infection.
      
Maximum Eligible Age:24 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:tumor response
Time Frame:day 28
Safety Issue:
Description:Frequency of CR with minimal residual disease negative bone marrow at day 28 and duration of remission

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:University of Pennsylvania

Last Updated

July 2, 2021