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

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02906371
• Collaborator: Children's Hospital of Philadelphia (Other)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 58.9
• Patients Per Site Per Month: 1.4

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Lymphoblastic Leukemia, Acute, Childhood	Drug: Tocilizumab; Drug: Tocilizumab; Biological: CART 19	Phase 1

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2016
• Actual Primary Completion Date: Mar 11, 2020
• Actual Study Completion Date: Jun 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tocilizumab high tumor burden 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).	Drug: Tocilizumab; 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.; Other Names: high tumor burden ; Biological: CART 19; 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.
Active Comparator: Tocilizumab low tumor burden 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).	Drug: Tocilizumab; Patients with ˂ 40% blasts in the bone marrow at pre-infusion (~ Day -5 to -1) will follow the standard CRS Rx algorithm; Other Names: low tumor burden ; Biological: CART 19; 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.

Outcome Measures

Primary Outcome Measures

1. the frequency of grade 4 CRS [from day 1 to 1 year]

   Frequency of CRS grade 4

Secondary Outcome Measures

1. tumor response [day 28]

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

Other Outcome Measures

1. CART19 cellular kinetics [from day -1 to year 1]

   Peak plasma concentration (Cmax) of CART19 cellular kinetic

2. Number of days in ICU [from day 0 through year one.]

3. Frequency of major medical interventions [from day 0 through year one.]

4. CART19 cellular kinetics [from day -1 through year 1]

   Area under the plasma concentration versus time curve (AUC)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 24 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

3. 2nd or greater marrow relapse OR

4. CNS relapse OR

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

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

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

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

9. 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

1. 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

1. 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)

2. 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.

3. Adequate organ function defined as:

4. 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

1. ALT ≤500 U/L

2. Bilirubin ≤2.0 mg/dl

3. 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

4. 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.

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

5. Pregnant or nursing (lactating) women. 8. Uncontrolled active infection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• Children's Hospital of Philadelphia

Investigators

• Principal Investigator: Stephan A Grupp, MD,PhD, Children's Hospital of Philadelphia

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02906371
• Other Study ID Numbers: 16CT022, 825445
• First Posted: Sep 20, 2016
• Last Update Posted: Jul 2, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Cytokine Release Syndrome

Study Results

No Results Posted as of Jul 2, 2021