Clinical Trials /

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

NCT03016377

Description:

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

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL
  • Official Title: Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1541-ATL
  • NCT ID: NCT03016377

Conditions

  • Acute Lymphoblastic Leukemia
  • Immune System Diseases
  • Immunoproliferative Disorders

Interventions

DrugSynonymsArms
iC9-CAR19 cellsCAR.CD19 T cellsExpansion Cohort Second Administration of iC9-CAR19 cells
RimiducidAP1903Expansion Cohort Second Administration of iC9-CAR19 cells
CyclophosphamideNeosarExpansion Cohort Second Administration of iC9-CAR19 cells
FludarabineFludaraExpansion Cohort Second Administration of iC9-CAR19 cells

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
iC9-CAR19 cellsExperimentalThe 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.
  • iC9-CAR19 cells
  • Rimiducid
  • Cyclophosphamide
  • Fludarabine
Expansion Cohort Second Administration of iC9-CAR19 cellsExperimentalAfter the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells.
  • iC9-CAR19 cells
  • Rimiducid
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        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)
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells
Time Frame:4 weeks
Safety Issue:
Description:Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).

Secondary Outcome Measures

Measure:Incidence of dose limiting toxicity to identify recommended phase 2 dose (RP2D)
Time Frame:4 weeks
Safety Issue:
Description:The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.
Measure:Changes in persistence of iC9-CAR19 T cells in vivo
Time Frame:15 years
Safety Issue:
Description:Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.
Measure:Overall Response Rate (ORR)
Time Frame:15 years
Safety Issue:
Description:ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm [defined as minimal residual disease negative complete response] by either flow cytometry or PCR analysis will be determined)
Measure:Overall survival after infusion of iC9-CAR19 T cells
Time Frame:15 years
Safety Issue:
Description:Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.
Measure:Event-free survival rate
Time Frame:15 years
Safety Issue:
Description:Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.
Measure:Relapse-free survival rate
Time Frame:15 years
Safety Issue:
Description:Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.
Measure:Incidence of patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE
Time Frame:15 years
Safety Issue:
Description:The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.
Measure:Changes in patient reported physical functions in adult patients
Time Frame:15 years
Safety Issue:
Description:Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.
Measure:Changes in patient reported health-related quality of life in adult patients
Time Frame:15 years
Safety Issue:
Description:Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.
Measure:Number of participants with adverse events as a measure of safety and tolerability of a second infusion of iC9-CAR19 T cells
Time Frame:4 weeks
Safety Issue:
Description:Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).
Measure:Rate of measurable residual disease (MRD) clearance in subjects who receive iC9-CAR19 T cells for MRD persistence or MRD-only relapse
Time Frame:8 weeks
Safety Issue:
Description:Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • CAR T cells
  • CD19
  • Leukemia
  • T Lymphocytes
  • AP1903
  • Cytokine Release Syndrome
  • Rimiducid
  • ICANS
  • Immune effector cell mediated neurotoxicity syndrome

Last Updated

February 24, 2020