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

Primary Purpose

Lymphoblastic Leukemia, Acute, Childhood

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tocilizumab
Tocilizumab
CART 19
Sponsored by
University of Pennsylvania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoblastic Leukemia, Acute, Childhood

Eligibility Criteria

1 Year - 24 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Tocilizumab high tumor burden

Tocilizumab low tumor burden

Arm Description

This 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).

This 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).

Outcomes

Primary Outcome Measures

the frequency of grade 4 CRS
Frequency of CRS grade 4

Secondary Outcome Measures

tumor response
Frequency of CR with minimal residual disease negative bone marrow at day 28 and duration of remission

Full Information

First Posted
August 29, 2016
Last Updated
June 30, 2021
Sponsor
University of Pennsylvania
Collaborators
Children's Hospital of Philadelphia
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1. Study Identification

Unique Protocol Identification Number
NCT02906371
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)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
August 2016 (undefined)
Primary Completion Date
March 11, 2020 (Actual)
Study Completion Date
June 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Pennsylvania
Collaborators
Children's Hospital of Philadelphia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoblastic Leukemia, Acute, Childhood

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tocilizumab high tumor burden
Arm Type
Active Comparator
Arm Description
This 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).
Arm Title
Tocilizumab low tumor burden
Arm Type
Active Comparator
Arm Description
This 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).
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
high tumor burden
Intervention Description
Patients with ≥ 40% blasts in the bone marrow at pre-infusion will be enrolled in the early tocilizumab cohort and will follow early CRS treatment algorithm.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
low tumor burden
Intervention Description
Patients with ˂ 40% blasts in the bone marrow at pre-infusion (~ Day -5 to -1) will follow the standard CRS Rx algorithm
Intervention Type
Biological
Intervention Name(s)
CART 19
Intervention Description
CART-19 cells transduced with a lentiviral vector to express either anti-CD19ζ scFv TCRζ:41BB, administered by i.v. injection using an intra-patient dose escalation approach: 10% on day 0, 30% on day 1 with a total dose goal of ~1.5 x107 - 5 x109 (~3x105 - 1x108/kg) T cells.
Primary Outcome Measure Information:
Title
the frequency of grade 4 CRS
Description
Frequency of CRS grade 4
Time Frame
from day 1 to 1 year
Secondary Outcome Measure Information:
Title
tumor response
Description
Frequency of CR with minimal residual disease negative bone marrow at day 28 and duration of remission
Time Frame
day 28
Other Pre-specified Outcome Measures:
Title
CART19 cellular kinetics
Description
Peak plasma concentration (Cmax) of CART19 cellular kinetic
Time Frame
from day -1 to year 1
Title
Number of days in ICU
Time Frame
from day 0 through year one.
Title
Frequency of major medical interventions
Time Frame
from day 0 through year one.
Title
CART19 cellular kinetics
Description
Area under the plasma concentration versus time curve (AUC)
Time Frame
from day -1 through year 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
24 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Relapsed or refractory B-cell ALL: 2nd or greater marrow relapse OR CNS relapse OR Any relapse after allogeneic hematopoietic stem cell (SCT) transplant and ≥ 4 months from SCT at enrollment OR Any relapse after CAR-modified T cell therapy OR Refractory disease defined as having not achieved an MRD-negative CR after ≥ 2 chemotherapy regimens/cycles (1 cycle for relapsed patients) OR Patients with Ph+ ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR 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 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 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) 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. Adequate organ function defined as: 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 ALT ≤500 U/L Bilirubin ≤2.0 mg/dl 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 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. 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. Age 1-29 years. Patients ages 24-29 years are eligible if their original leukemia diagnosis was prior to age 21. Adequate performance status (Lansky or Karnofsky score ≥50). Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3. Exclusion Criteria: Active hepatitis B or active hepatitis C. HIV Infection. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephan A Grupp, MD,PhD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36351239
Citation
Newman H, Li Y, Liu H, Myers RM, Tam V, DiNofia A, Wray L, Rheingold SR, Callahan C, White C, Baniewicz D, Winestone LE, Kadauke S, Diorio C, June CH, Getz KD, Aplenc R, Teachey DT, Maude SL, Grupp SA, Bona K, Leahy AB. Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy. Blood. 2023 Feb 9;141(6):609-619. doi: 10.1182/blood.2022017866.
Results Reference
derived
PubMed Identifier
33417474
Citation
Kadauke S, Myers RM, Li Y, Aplenc R, Baniewicz D, Barrett DM, Barz Leahy A, Callahan C, Dolan JG, Fitzgerald JC, Gladney W, Lacey SF, Liu H, Maude SL, McGuire R, Motley LS, Teachey DT, Wertheim GB, Wray L, DiNofia AM, Grupp SA. Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol. 2021 Mar 10;39(8):920-930. doi: 10.1200/JCO.20.02477. Epub 2021 Jan 8.
Results Reference
derived
Links:
URL
http://www.chop.edu/service/oncology/pediatric-cancer-research/cart-19-trial.html
Description
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Study of the Tocilizumab Optimization Timing for CART19 Associated Cytokine Release Syndrome

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