Tocilizumab for the Treatment of CART19 Associated Cytokine Release Syndrome in Patients with CD19 Positive Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia or B-cell Lymphoblastic Lymphoma
- 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.
- Relapsed or refractory B-cell acute lymphoblastic leukemia (ALL): * 2nd or greater marrow relapse OR * Central nervous system (CNS) relapse OR * Any relapse after allogeneic hematopoietic stem cell transplantation (HSCT) and >= 4 months from stem cell transplant (SCT) at enrollment OR * Any relapse after chimeric antigen receptor (CAR)-modified T cell therapy OR * Refractory disease defined as having not achieved an minimal residual disease (MRD)-negative complete remission (CR) after >= 2 chemotherapy regimens/cycles (1 cycle for relapsed patients) OR * Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR * 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 * 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 * Patients with prior or current history of CNS3 disease will be eligible if CNS disease is responsive to therapy
- Documentation of CD19 tumor expression in bone marrow, peripheral blood, cerebral spinal fluid (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
- A serum creatinine based on age/gender as follows: * Age 1 to < 2 years: male =< 0.6 mg/dL, female =< 0.6 mg/dL * Age 2 to < 6 years: male =< 0.8 mg/dL, female =< 0.8 mg/dL * Age 6 to < 10 years: male =< 1.0 mg/dL, female =< 1.0 mg/dL * Age 10 to < 13 years: male =< 1.2 mg/dL, female =< 1.2 mg/dL * Age 13 to < 16 years: male =< 1.5 mg/dL, female =< 1.4 mg/dL * Age >= 16 years: male =< 1.7 mg/dL, female =< 1.4 mg/dL
- Alanine aminotransferase (ALT) =< 500 U/L
- Bilirubin =< 2.0 mg/dl
- Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea, pulse oximetry > 92% on room air; carbon monoxide diffusing capability test (DLCO) >= 40% (corrected for anemia) if pulmonary function tests (PFTs) are clinically appropriate as determined by the treating investigator
- Left ventricular shortening fraction (LVSF) >= 28% or ejection fraction (LVEF) >= 40% confirmed by echocardiography (ECHO), or adequate ventricular function documented by a scan or a cardiologist
- 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
- Patients ages 24-29 years are eligible if their original leukemia diagnosis was prior to age 21
- Adequate performance status (Lansky or Karnofsky score >= 50)
- Subjects of reproductive potential must agree to use acceptable birth control methods
- Active hepatitis B or active hepatitis C
- Human immunodeficiency virus (HIV) infection
- Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy
- CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity
- Pregnant or nursing (lactating) women
- Uncontrolled active infection
I. To describe the frequency of grade 4 cytokine release syndrome (CRS).
I. To describe tumor response.
II. To describe tisagenlecleucel (CART19) cellular kinetics.
III. Additional safety endpoints.
I. To compare rate of CART19 expansion before and after first tocilizumab dose.
II. To describe the profile of soluble immune factors that may be key to cytokine release syndrome.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients undergo leukapheresis during weeks -4 to -3 and receive chemotherapy at the discretion of treating physician 1 week prior to tisagenlecleucel infusion. Within 1-4 days of chemotherapy completion, patients receive tisagenlecleucel intravenously (IV) on days 0 and 1. Patients with >= 40% blasts in bone marrow at pre-infusion also receive early timing tocilizumab IV over 1 hour in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo leukapheresis during weeks -4 to -3 and receive chemotherapy at the discretion of treating physician 1 week prior to tisagenlecleucel infusion. Within 1-4 days of chemotherapy completion, patients receive tisagenlecleucel IV on days 0 and 1. Patients with < 40% blasts in bone marrow at pre-infusion also receive standard of care timing tocilizumab IV over 1 hour in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at day 28, monthly for 6 months, and then every 3 months for up to 1 year.
Trial Phase Phase O
Trial Type Treatment
Children's Hospital of Philadelphia
- Primary ID 16CT022
- Secondary IDs NCI-2019-05349, 16-013097
- Clinicaltrials.gov ID NCT02906371