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

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

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.