Clinical trial NCT02906371: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoblastic Leukemia, Acute, Childhood
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
First posted: 2016-09-20
Enrollment: 80
Sex: ALL
Minimum age (years): 1
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: the frequency of grade 4 CRS
timeFrame: from day 1 to 1 year
Secondary outcomes:
measure: tumor response
timeFrame: day 28
Other outcomes:
measure: CART19 cellular kinetics
timeFrame: from day -1 to year 1
measure: Number of days in ICU
timeFrame: from day 0 through year one.
measure: Frequency of major medical interventions
timeFrame: from day 0 through year one.
measure: CART19 cellular kinetics
timeFrame: from day -1 through year 1
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Stephan A Grupp, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.