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

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)

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).

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:

   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.