CD19-CAR T-cell Immunotherapy in Treating Patients with CD19-Positive Leukemia

Inclusion Criteria

• Must be >= 10 kg
• CD19+ leukemia or lymphoma
• PHASE I (leukemia only): If post allogeneic HCT: Confirmed CD19+ leukemia recurrence defined as >= 0.01% disease by Seattle Children’s Hospital (SCH) or University of Washington (UW) Pathology Department following allogeneic HCT
• PHASE I (leukemia only): If relapse/refractory status with no prior history of allogeneic HCT (one of the following) * 2nd or greater marrow relapse, with or without extramedullary disease * 1st marrow relapse at end of 1st month of re-induction with marrow having >= 0.01% blast by morphology and/or MPF, with or without extramedullary disease * Primary refractory as defined as having M2 or M3 marrow after 2 or more separate induction regimens * Subject has indication for HCT but has been deemed ineligible
• PHASE II (leukemia): Subject status post allogeneic HCT: * Recurrent CD19+ leukemia defined as >= 0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT
• PHASE II (leukemia): Subject with no prior history of allogeneic HCT (one of the following): * 2nd or greater relapse, with or without extramedullary disease (isolated extramedullary disease is eligible) * 1st marrow relapse at end of 1st month of re-induction with marrow having >= 0.01% blast disease, with or without extramedullary disease * Primary refractory as defined as having M2 or M3 marrow after induction * Subject has indication for HCT but has been deemed ineligible
• PHASE II (leukemia): Marrow involvement * For those subjects with marrow involvement, the first 15 subjects enrolled after the 03.28.2017 amendment must have detectable disease at the time of enrollment (this criterion was satisfied as of 1 September 2017)
• PHASE II (lymphoma): CD19+ non-Hodgkin lymphoma (NHL) refractory or relapsed with no known curative therapies available
• Patients with central nervous system (CNS) involvement are eligible provided that they are asymptomatic and in the opinion of the study principal investigator (PI) have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion; patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization
• Lansky performance status score of >= 50 or a Karnofsky score of >= 50 for patients >= 16 years of age; Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Life expectancy of > 8 weeks
• All patients must discontinue all anti-cancer agents and radiotherapy, and, in the opinion of the study PI, have sufficiently recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. * Chemotherapy: Must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy which can be administered at any given time pre study or upon enrollment nor does it include maintenance chemotherapy for the subset of patients who relapse during maintenance) ** For patients who were previously enrolled on the trial but were removed prior to receiving T cell therapy and are re-enrolling on the trial and already have a usable T cell product generated during previous enrollment, the duration and chemotherapy agents used is not restricted. * Immunotherapy directed at leukemia: No antibodies within 3 half-lives prior to study enrollment (applicable to phase 1 only). * Steroids: No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment. * Gene-Modified Cells: No prior genetically modified cell therapy that is still detectable or virotherapy allowed; patients who are otherwise eligible but have detectable circulating CAR T cells of < 5% will be eligible,but will be evaluated as a separate strata from CAR-naive patients in the phase 2 portion of the study
• Adequate renal function defined as: a serum creatinine that is =< maximum based on age/gender Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 Age: 2 years < 6 years; maximum serum creatinine (mg/dL): 0.8 Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1.0 Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 Age: 13 to < 16 years; maximum serum creatinine (mg/dL):1.5 (male) 1.4 (female) Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female)
• Total bilirubin: =< 3 X upper limit of normal (ULN) for age OR conjugated bilirubin =< 2 mg/dl
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 5 X the upper limit of normal (ULN)
• Shortening fraction > 28% by echocardiogram or ejection fraction of > 50 % by multigated acquisition (MUGA)
• Oxygen saturation >= 90% on room air without supplemental oxygen or mechanical ventilation
• Absolute lymphocyte count (ALC) >= 100 cells/ul
• Documented negative human immunodeficiency infection virus (HIV) antigen and antibody, hepatitis B surface antigen, and hepatitis C antibody within 3 months prior to enrollment; for patient with positive hepatitis C antibody (Ab), negative polymerase chain reaction (PCR) testing must be documented in order to be eligible
• PHASE I: For the post allo-HCT cohort, chimerism analysis must demonstrate > 95% either donor or recipient in peripheral blood CD3 cells, must be done within 1 month of enrollment (no mixed chimerism are eligible)
• Able to tolerate apheresis procedure, including placement of temporary apheresis line if required
• Willing to participate in long-term follow-up for up to 15 years if enrolled in the study and receive T-cell infusion
• Subjects of childbearing/fathering potential must agree to use highly effective contraception from the time of initial T cell infusion through 12 months following the last T cell infusion
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Research participant without clinically significant encephalopathy/new focal neurologic deficits
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Research participant with no current evidence of active GVHD
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Subject has been without supra-physiologic dosing of systemic corticosteroids for at least 7 days prior to planned T cell infusion
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Adequate respiratory function defined as not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Absolute lymphocyte count < 500/ul or subject has received lymphodepleting chemotherapy administered at least 48 hours prior to T cell infusion.
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Adequate renal function defined as: a serum creatinine that is =< maximum based on age/gender * Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 * Age: 2 years < 6 years; maximum serum creatinine (mg/dL): 0.8 * Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1.0 * Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 * Age: 13 to < 16 years; maximum serum creatinine (mg/dL):1.5 (male) 1.4 (female) * Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female)
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Total bilirubin: =< 3 x ULN for age OR conjugated bilirubin =< 2 mg/dL
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: ALT (SGPT): =< 5 x ULN
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Patients must NOT have an active severe infection defined as: * A positive blood culture within 48 hours of scheduled T cell infusion OR * A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell infusion
• ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: If a patient has received anthracycline chemotherapy after enrollment, they must have an echocardiogram to demonstrate shortening fraction > 28% or MUGA to demonstrate ejection fraction of > 50%. The echocardiogram or MUGA can be done at any time following the anthracycline (does NOT need to be within 48 hours of the T cell infusion)
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has tolerated prior dose of modified T cell infusion without experiencing a dose limiting toxicity OR if patient did have a dose limiting toxicity (DLT), they have fully recovered back to baseline
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has modified T cell product available for release
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has < 5 % detectable modified T cells in peripheral blood (can be done at any time prior)
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has evidence of persistence of CD19+ malignant cells OR has CD19+ B cell recovery detected within 1 year of initial T cell infusion
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Research participant without clinically significant encephalopathy/new focal neurologic deficits
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Oxygen saturation 90% or higher on room air
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Adequate renal function defined as: a serum creatinine that is =< maximum based on age/gender Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 Age: 2 years < 6 years; maximum serum creatinine (mg/dL): 0.8 Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1.0 Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 Age: 13 to < 16 years; maximum serum creatinine (mg/dL):1.5 (male) 1.4 (female) Age: > 16 years; maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female)
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Total bilirubin: =< 3 x ULN for age OR conjugated bilirubin =< 2 mg/dL
• RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: ALT (SGPT): =< 5 x ULN

Exclusion Criteria

• Presence of active clinically significant CNS dysfunction (including but not limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
• Pregnant or breast-feeding
• If status post allogeneic HCT, presence of active graft versus host disease (GVHD) or receiving immunosuppressive GVHD therapy within 4 weeks prior to enrollment
• Presence of an active malignancy other than CD19+ leukemia
• Presence of an active severe infection defined as: * A positive blood culture within 48 hours of study enrollment * A fever above 38.2 Celsius (C) AND clinical signs of infection within 48 hours of study enrollment
• Presence of any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial
• RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Research participant with current evidence of GVHD
• RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Patient requiring supplemental oxygen or mechanical ventilation
• RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Patients has an active severe infection defined as: * A positive blood culture within 48 hours of scheduled T cell infusion OR * A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell infusion