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

Lymphoblastic Leukemia, Acute, Childhood Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT02906371
• Other study ID #: 16CT022, 825445
• Status: Completed
• Phase: Phase 1
• Start date: August 2016
• Est. completion date: June 30, 2021

Study information

• Verified date: June 2021
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: June 30, 2021
• Est. primary completion date: March 11, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 24 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Leukemia, Acute, Childhood
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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.
• Tocilizumab
Patients with ? 40% blasts in the bone marrow at pre-infusion (~ Day -5 to -1) will follow the standard CRS Rx algorithm

Biological:
• CART 19
CART-19 cells transduced with a lentiviral vector to express either anti-CD19? scFv TCR?: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.

Locations

Country	Name	City	State
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	Children's Hospital of Philadelphia

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CART19 cellular kinetics	Peak plasma concentration (Cmax) of CART19 cellular kinetic	from day -1 to year 1
Other	Number of days in ICU		from day 0 through year one.
Other	Frequency of major medical interventions		from day 0 through year one.
Other	CART19 cellular kinetics	Area under the plasma concentration versus time curve (AUC)	from day -1 through year 1
Primary	the frequency of grade 4 CRS	Frequency of CRS grade 4	from day 1 to 1 year
Secondary	tumor response	Frequency of CR with minimal residual disease negative bone marrow at day 28 and duration of remission	day 28

External Links

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