Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL

Inclusion Criteria

• •All clinical and laboratory data required for determining eligibility must be available in the subject's medical/research record which will serve as the source document. Subjects may be transfused with blood products to obtain a hemoglobin level \> 7.0 g/dL and platelet count \> 20,000 per μl.
• •Written informed consent for procurement signed by the subject or the legal guardian of a pediatric subject and HIPAA authorization
• •Age 3 to 17 years of age for pediatric subjects (weight must be ≥10 kg), ≥ 18 to 70 years of age for adults at the time of consent.
• •Karnofsky score \> 60%, if ≥16 years old, or Lansky performance score of greater than 60% if \<16 years old .
• •Demonstrate adequate renal and hepatic function as defined below; all screening labs to be obtained within 72 hours prior:
• •System Laboratory Value Renal\* Serum Creatinine (sCr) ≤ 1.5 × ULN) Hepatic: Total bilirubin (tBili) ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome Aspartate aminotransferase (AST) ≤ 3.0 × ULN Alanine aminotransferase (ALT) ≤ 3.0 × ULN
• •Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to procurement. Note: Females are considered of childbearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• •Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use two forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Female participants will inform their male partners that they must use the methods of birth control required by the protocol.
• •Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures.
• •Relapsed or refractory precursor B cell ALL:
• •* 2nd or greater bone marrow or central nervous system (CNS) relapse,
• •* Any bone marrow or CNS relapse \>100 days after allogeneic stem cell transplant, Primary refractory ALL defined as no complete response after 2 cycles of a standard of care chemotherapy regimen, or
• •* For adult subjects: first bone marrow or CNS relapse with duration of first CR \<1 year, or CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of relapse
• •* Subjects with isolated non-CNS extramedullary disease will be eligible as long as the time-of-remission criteria above for bone marrow and CNS relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression
• •* For pediatric subjects: first bone marrow, CNS or isolated non-CNS extramedullary relapse refractory to more than 1 cycle of standard therapy for relapsed ALL
• •* While active CNS3 leukemia will be excluded, subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment will be allowed to participate. Intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion.
• •* Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible. Intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
• •* Subjects who have previously achieved remission with no detectible measurable residual disease (MRD) by multi-parameter flow cytometry, and who have re- developed CD19+ MRD measured by multi-parameter flow cytometry will be eligible, provided that the duration of first MRD-negative CR was \<1 year, MRD- negative CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of MRD recurrence, or MRD reappearance occurs during second or subsequent CR.
• •* Subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after one or more cycles of blinatumomab.
• •CD19 positivity of lymphoblasts confirmed by flow cytometry or IHC per institutional standards.
• •Life expectancy ≥ 12 weeks.
• •Demonstrate adequate renal and hepatic function as defined below; all screening labs to be obtained within 72 hours prior to procurement.
• •\*For pediatric patients, adequate renal function is defined as below: Age Maximum Serum Creatinine (mg/dL) Both (Male, Female) 3 to \<6 years ≤0.8 6 to \<10 years ≤1 10 to \<13 years ≤1.2 13 to \<16 years (Male) ≤1.5 / Female ≤1.4 16 to \<18 years (Male) ≤1.7 / Female ≤1.4
• •Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to procurement is left to the discretion of the investigator. Maintenance doses of systemic chemotherapy are defined as methotrexate ≤30 mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. Maintenance therapy in patients with Ph+ leukemia may also contain tyrosine kinase inhibitors (TKIs) targeting BCR-ABL, at the discretion of the investigator. Corticosteroid- containing maintenance therapy is permitted only if corticosteroids are administered \>14 days prior to procurement.
• •Relapsed or refractory precursor B cell ALL, confirmed by presence of blasts in the blood or bone marrow (≥5%) or in any extramedullary site. Subjects who have previously achieved remission with no detectible measurable residual disease (MRD) by multi- parameter flow cytometry, and who have re-developed CD19+ MRD measured by multi- parameter flow cytometry are eligible, provided that the duration of first MRD-negative CR was \<1 year, MRD-negative CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of MRD recurrence/relapse, or MRD-recurrence in second or subsequent morphologic CR. Additionally, subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after one or more cycles of blinatumomab are eligible to participate. Because CNS leukemia is not curable with conventional therapies, subjects who met inclusion criterion for CNS leukemia at the time of procurement will be eligible for lymphodepletion even if intrathecal or systemic chemotherapy has rendered their cerebrospinal fluid free of lymphoblasts prior to lymphodepletion.
• •Life expectancy ≥ 12 weeks.
• •Subjects who have received prior therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion on this study.
• •Demonstrate adequate renal and hepatic function as defined below; all screening labs to be obtained within 72 hours prior to lymphodepletion.
• •For pediatric patients, adequate renal function is defined as below:
• •Age Maximum Serum Creatinine (mg/dL) Both Male/Female 3 to \<6 years ≤0.8 6 to \<10 years ≤1 10 to \<13 years ≤1.2 13 to \<16 years (Male) ≤1.5/ (Female) ≤1.4 16 to \<18 years (Male) ≤1.7/(Female) ≤1.4
• •As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures.
• •As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures.
• •Life expectancy ≥ 12 weeks.
• •Documentation of absence of human anti-mouse antibodies (HAMA). Demonstrate adequate renal and hepatic function as defined below; all screening labs to be obtained within 72 hours prior to lymphodepletion.
• •Subject meets at least one of the following criteria:
• •B-cell recovery (defined as absolute CD19+ cell count of \>50/μL in the blood or bone marrow CD19+ B cells ≥0.5% of marrow aspirate cells by flow cytometry) within 6 months of initial infusion. Subjects who meet this criteria within 6 months of initial infusion may be started on lymphodepletion at a date later than 6 months from initial infusion.
• •MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with CD19+ expression at any time after initial infusion.
• •At least 4 weeks have passed since the initial iC9-CAR19 T cell infusion.
• •Subjects have resolved/recovered symptoms from CRS and/or ICANS that developed after prior iC9-CAR19 T cell infusion.
• •Subjects must have autologous transduced activated T cells that meet the Certificate of Analysis (CofA) acceptance criteria. The subject must have sufficient available cells or have sufficient stored peripheral blood to manufacture additional iC9-CAR19 T cells.