Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL
Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL
The body has different ways of fighting infection and disease. No single way is effective at
 fighting cancer. This research study combines two different ways of fighting disease:
 antibodies and T cells. Antibodies are proteins that protect the body from disease caused by
 bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which
 stops them from growing and causing bad effects. T cells, also called T lymphocytes, are
 special infection-fighting blood cells that can kill other cells, including tumor cells or
 cells that are infected. Both antibodies and T cells have been used to treat patients with
 cancers. They both have shown promise, but neither alone has been sufficient to cure most
 patients. This study combines both T cells and antibodies to try to create a more effective
 treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen
 receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.

 In previous studies, it has been shown that a new gene can be put into T cells that will
 increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes
 make up the chemical structure carrying your genetic information that may determine human
 characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells
 makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and
 can find and stick to leukemia cells because these leukemia cells have a substance on their
 surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but
 have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has
 been changed so that instead of floating free in the blood a piece of it is now joined to the
 surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is
 attached to the T cells instead of the entire antibody. When an antibody is joined to a T
 cell in this way it is called a chimeric receptor. These CD19 chimeric (combination)
 receptor-activated T cells kill some of the tumor, but they do not last very long in the body
 and so their chances of fighting the cancer are unknown.

 Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging;
 however, many subjects receiving this treatment have experienced unwanted side effects
 including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm
 or an infusion reaction). Cytokines are small proteins that aract as e signals to other cells
 and are the way cells talk to one another. During cytokine release syndromesyndrome, too many
 cytokines are released and too many cells in your body react to their release. Symptoms
 resulting from cytokine release syndrome vary from flu-like symptoms to more severe side
 effects such as cardiac arrest, multi-system organ failure or death. We predict that about
 50% of patients on this study will experience mild to severe cytokine release syndrome.

 To help reduce cytokine release syndrome symptoms in future patients, a safety switch has
 been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to
 sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19
 cells with the safety switch are referred to as iC9-CAR19 cells.

 The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and
 tolerable (there are not too many unwanted effects). If you experience severe cytokine
 release syndrome or moderate to severe cytokine release syndrome that does not get better
 once you are given standard treatments, you may be given a second study drug called
 rimiducid. Similar studies showed that rimiducid can to turn on the safety switch, iC9 in
 other therapies. Using rimiducid to activate the safety switch may be done in addition to
 treating you according to hospital guidelines and making all efforts to immediately attend to
 your cytokine release syndrome symptoms
OUTLINE

 Cell Procurement

 Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects
 for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a
 leukopheresis may be performed to isolate sufficient T cells. The parameters for apheresis
 will be up to 2 blood volumes.

 Lymphodepleting Regimen

 Subjects will receive a lymphodepleting regimen of fludarabine 25 mg/m2/day administered IV
 over 30 min for three consecutive days and a single IV dose of cyclophosphamide 900 mg/m2
 administered over 1 hour on the fourth day. If iC9-CAR19 T cell infusion is delayed for >4
 weeks, lymphodepletion may be repeated prior to iC9-CAR19 T cell infusion.

 Administration of iC9-CAR19 T Cells

 Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
 receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy
 regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified. A phase
 I trial performed by Lee et al established that 1×106 CAR19+ T cells/kg was safe and
 associated with significant in vivo expansion and we anticipate similar results with
 iC9-CAR19+ T cells.

 Second Cell Infusion Requirements:

 Subjects will be offered a second infusion based on B-cell recovery and MRD status >4 weeks
 after the initial infusion if cells are available or if the subject has sufficient stored
 peripheral blood to manufacture additional iC9-CAR19 T cells.

 Duration of Therapy

 Therapy in LCCC1541-ATL involves 1 infusion of iC9-CAR19 cells. Treatment with one infusion
 will be administered unless:

 -  Subject decides to withdraw from study treatment, or

 -  General or specific changes in the subject's condition render the subject unacceptable
 for further treatment in the judgment of the investigator.

 A second infusion with prior lymphodepletion will be given to subjects enrolled in the
 expansion cohort and to subjects enrolled in the dose escalation cohort once the RP2D is
 reached if they meet the eligibility requirements for lymphodepletion and infusion.
 Specifically, only subjects with the following characteristics will be offered a second
 infusion:

 -  B-cell recovery (defined as absolute CD19+ cell count >50/μL in the blood or bone marrow
 within 6 months of initial infusion AND/OR

 -  MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with
 CD19+ expression at any time after the initial infusion.

 -  *Note that subjects who receive dose level 1 in the dose escalation will receive the
 RP2D for their second infusion, if applicable.

 Duration of Follow-up

 Subjects will be followed for up to 15 years after the final iC9-CAR19 T-cell infusion for
 RCR evaluation or until death, whichever occurs first. Subjects removed from study for
 unacceptable adverse events will be followed until resolution or stabilization of the adverse
 event.

 Subjects who receive new therapy (such as hematopoietic stem cell transplant) after a cell
 product administration will still be required to complete abbreviated follow up procedures.
Inclusion Criteria - Cell Procurement

 -  Written informed consent for procurement signed by subject/legal guardian of pediatric
 subject and HIPAA authorization

 -  Age 3-17 years of age for pediatric subjects (weight must be ≥10 kg), ≥18-70 years of
 age for adults at time of consent

 -  Karnofsky score >60% (≥16 years old), Lansky performance score of >60% (<16 years old)

 -  Relapsed or refractory (R/R) precursor B cell ALL:

 -  2nd or greater bone marrow relapse, or

 -  Any bone marrow relapse >100 days after allogeneic stem cell transplant, or

 -  Primary refractory ALL defined as no complete response (CR) after 2 cycles of
 standard of care chemotherapy regimen, or

 -  For adult subjects: 1st bone marrow relapse with 1st CR <1 year, or CR1 ≥1 year
 and refractory to ≥1 cycle of therapy for relapse

 -  Subjects with isolated non-CNS extramedullary disease will be eligible as long as
 the time-of-remission criteria (above) are met and biopsy for extramedullary
 disease confirms CD19 expression

 -  For pediatric subjects: 1st bone marrow or isolated non-CNS extramedullary
 relapse refractory to 1 cycle of standard therapy for relapsed ALL

 -  While active CNS3 leukemia is excluded, subjects with concurrent CNS3 disease and
 bone marrow relapse who responded to CNS-directed therapy prior to enrollment may
 participate. Intrathecal chemotherapy will be allowed to continue between
 lymphodepleting chemotherapy (LD) and cell infusion.

 -  Subject with CNS2 disease and concurrent bone marrow relapse are eligible.
 Intrathecal chemotherapy will be allowed to continue between LD and cell infusion

 -  Subject previously achieving remission with no detectable measurable residual
 disease (MRD) by multi-parameter flow cytometry, and who re-developed CD19+ MRD
 measured by multi-parameter flow cytometry will be eligible, provided the 1st
 MRD-negative CR was <1 year, MRD-negative CR1 duration ≥1 year and refractory to
 ≥1 cycle of therapy for MRD recurrence, or MRD reappearance occurs during
 2nd/subsequent CR

 -  Subject with persistent CD19+ MRD measured by multi-parameter flow cytometry
 after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after
 ≥1 cycles of blinatumomab

 -  Subject with Ph+ ALL will be eligible if failed ≥2 ABL tyrosine kinase inhibitors
 (TKI) or relapsed after allogeneic stem cell transplant, or have CD19+ MRD. Subject
 with the T315I ABL kinase point mutation eligible if have failed ponatinib-containing
 therapy, regardless of number of prior ABL TKIs

 -  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:

 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

 *For pediatric patients, adequate renal function defined below: Age: Maximum sCr (mg/dL)
 (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13 years: ≤1.2,
 ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4

 -  Females of childbearing potential (WOCBP) must have a negative serum pregnancy test
 prior to procurement. Note: Females are considered of childbearing potential unless
 are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal
 ligation, or bilateral oophorectomy) or 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 2 effective methods of contraception from informed
 consent until 3 months after end of treatment. The 2 contraception methods can be
 comprised of 2 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 1st dose of study therapy through 3 months after the last
 dose of study therapy. As determined by enrolling physician/designee, ability of
 subject to understand and comply with study procedures

 -  Subject currently receiving "maintenance" doses of chemotherapy eligible and need for
 intrathecal prophylaxis prior to procurement is per investigator discretion.
 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 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

 Exclusion Criteria - Cell Procurement

 -  Subject with relapsed fulminant CD19+ ALL rapidly progressing with circulating
 lymphoblasts that are rising in proportion to >50% of circulating white blood cells

 -  Lumbar puncture must be performed prior to procurement and subject with evidence of
 CNS3 disease will be excluded from study entry. Subject with concurrent CNS3 disease
 and bone marrow relapse who responded to CNS-directed therapy prior to enrollment/LD
 allowed to participate. Subject with CNS2 disease and concurrent bone marrow relapse
 are eligible. Intrathecal chemotherapy will be allowed to continue between cell
 procurement and LD

 -  Pregnant/breastfeeding (Note: breast milk cannot be stored for future use if collected
 while the mother is being treated on study)

 -  Has known active and/or progressive additional malignancy requiring treatment;
 exceptions include basal cell or squamous cell skin cancer, in situ cervical or
 bladder cancer, other cancer for which the subject has been disease-free for ≥5 years

 -  Subject must not have tumor in a location where enlargement could cause airway
 obstruction

 -  Subject may not have an oxygen requirement as defined by pulse oximetry of <90% on
 room air

 -  Subject must not have left ventricular ejection fraction of <40% (shortening fraction
 <27% for pediatric subjects) as measured by echo or MUGA

 -  Patient with the following infections will be excluded: active HIV, HTLV, HBV, HCV.
 Note: To meet eligibility subjects must not be positive for HIV antibody or HIV viral
 load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for
 Hep B surface antigen, or negative for HCV antibody or HCV viral load

 -  Patient on treatment for other active uncontrolled infections with resolution of
 signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory
 infections are not excluded. Other active uncontrolled infections will be excluded

 -  Prior to procurement current use of systemic corticosteroids at doses ≥10 mg/day
 prednisone/equivalent; those receiving <10 mg/day may be enrolled at discretion of
 investigator. Corticosteroid use is contraindicated following iC9-CAR19 infusion
 unless medically necessary e.g., to treat CRS. Physiologic replacement with
 hydrocortisone is allowed at doses 6-12 mg/m2/day, or equivalent

 -  Received anti-CD19 antibody-based therapy or cytotoxic chemotherapy not described as
 maintenance therapy in inclusion 4.1.12 within 2 weeks of procurement

 Inclusion Criteria - Lymphodepletion (LD)

 -  Written informed consent for the main study signed by subject/legal guardian of
 pediatric subject.

 -  R/R precursor B cell ALL, confirmed by presence of blasts in the blood or bone marrow
 (≥5%) or in any extramedullary site. Subject who previously achieved remission with no
 detectable MRD by multi-parameter flow cytometry and re-developed CD19+ MRD measured
 by multi-parameter flow cytometry are eligible, provided 1st MRD-negative CR was <1
 year, MRD-negative CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for MRD
 recurrence/relapse, or MRD-recurrence in 2nd or subsequent morphologic CR. Subjects
 with persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of
 initial chemotherapy and have persistence of CD19+ MRD after ≥1 cycles of blinatumomab
 are eligible

 -  Karnofsky score >60%, (≥16 years old)/Lansky performance score >60% (if <16 years old)

 -  Life expectancy ≥12 weeks

 -  If prior therapy with murine antibodies must have documentation of absence of human
 anti-mouse antibodies (HAMA) prior to LD on this study

 -  Demonstrate adequate renal and hepatic function as defined below System Laboratory
 Value Renal*: sCr ≤1.5 × ULN Hepatic: tBili ≤1.5 × ULN, unless attributed to Gilbert's
 Syndrome; AST ≤ 3.0 × ULN; ALT ≤3.0 × ULN

 *For pediatric patients, adequate renal function defined below: Age: Maximum sCr
 (mg/dL) (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13
 years: ≤1.2, ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4

 -  WOCBP must have a negative serum pregnancy test

 -  Females and males of childbearing potential must be willing to abstain from
 heterosexual activity or to use 2 forms of effective methods of contraception from the
 time of informed consent until 3 months after treatment discontinuation. The 2
 contraception methods can be comprised of 2 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 1st dose of study therapy through 3 months after the last
 dose of study therapy

 -  As determined by the enrolling physician/designee, ability of the subject to
 understand and comply with study procedures

 -  For subjects who receive chemotherapy between cell procurement and LD, washout periods
 between chemotherapy and the beginning of LD will be required

 -  Subjects must have autologous transduced activated T cells that meet the Certificate
 of Analysis (CofA) acceptance criteria

 Exclusion Criteria - Lymphodepletion (LD)

 -  Pregnant/breastfeeding (Note: breast milk cannot be stored for future use if collected
 while the mother is being treated on study)

 -  Has a known additional malignancy that is active and/or progressive requiring
 treatment; exceptions include basal cell or squamous cell skin cancer, in situ
 cervical or bladder cancer, or other cancer for which the subject has been
 disease-free for at least 5 years

 -  Subjects must not have tumor in a location where enlargement could cause airway
 obstruction

 -  Subjects may not have an oxygen requirement as defined by pulse oximetry of <90% on
 room air

 -  Treatment with any investigational drug within 14 days prior to LD or has received any
 tumor vaccines within the previous 5 weeks prior to LD

 -  Subject received pegylated-asparaginase ≤3 weeks prior to LD

 -  Radiotherapy to a non-CNS site completed <1 week prior to LD, or CNS directed
 radiation completed <7 weeks prior to LD

 -  Subject receiving following drugs <1 week prior to LD: salvage chemotherapy (e.g.
 clofarabine, cytosine arabinoside >100 mg/m2, anthracyclines, cyclophosphamide,
 methotrexate ≥25 mg/m2)

 -  Any systemic drug used for GVHD must be stopped >3 weeks prior to LD (e.g. calcineurin
 inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin,
 thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF,
 anti-IL6 or anti-IL6R, systemic steroids)

 -  The following drugs must be stopped prior to the beginning of LD: TKIs, hydroxyurea,
 vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate <25 mg/m2, cytosine
 arabinoside <100 mg/m2/day, and asparaginase (non-pegylated). These drugs should not
 be administered concomitantly or following LD

 -  CNS prophylaxis with intrathecal methotrexate, cytarabine and/or hydrocortisone
 treatment must be stopped prior to LD

 -  Patients with the following systemic viral infections will be excluded: active HIV,
 HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV
 antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for
 HTLV1 and 2, negative for Hep B surface antigen, or negative for HCV antibody or HCV
 viral load

 -  Patients who are on treatment for other active uncontrolled infections with resolution
 of signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory
 infections are not excluded. Other active uncontrolled infections will be excluded

 -  Use of systemic corticosteroids at doses ≥10 mg/day prednisone or its equivalent;
 those receiving <10 mg/day may be enrolled at discretion of investigator. Physiologic
 replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent

 Inclusion Criteria- iC9-CAR19 Cell Infusion

 -  Females and males of childbearing potential must be willing to abstain from
 heterosexual activity or to use 2 forms of effective methods of contraception from
 informed consent until 3 months after treatment discontinuation. The 2 contraception
 methods can be comprised of 2 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 first dose of study therapy through 3 months after the last dose
 of study therapy

 -  As determined by the enrolling physician/designee, ability of the subject to
 understand and comply with study procedures

 Exclusion Criteria- iC9-CAR19 Cell Infusion

 -  Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically
 necessary (e.g., to treat CRS)

 -  Severe systemic uncontrolled disease or toxicities that develop after LD may prompt
 exclusion from cell infusion at the discretion of the investigator

 -  Received any donor lymphocyte infusions (DLI) ≤6 weeks prior to cell infusion

 -  Received any T cell lytic or toxic antibody (e.g. alemtuzumab) ≤8 weeks prior to cell
 infusion (residual lytic levels may destroy the infused iC9-CAR19 T cells and/or
 prevent their in vivo expansion)