Clinical Trials /

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

NCT03016377

Description:

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. 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 seem to 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 have shown that many subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome. In this study, to help reduce cytokine release syndrome symptoms, the ATLCAR.CD19 cells have a safety switch that when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome to mild, but still allows the remaining iC9-CAR19 cells to effectively fight the leukemia. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable and and later to determine an optimal dose of AP1903 to be given to subjects to alleviate severe cytokine release syndrome.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
  • 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 cellsiC9-CAR19 cells
AP1903RimiducidiC9-CAR19 cells
CyclophosphamideNeosariC9-CAR19 cells
FludarabineFludaraiC9-CAR19 cells

Purpose

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. 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 seem to 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 have shown that many subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome. In this study, to help reduce cytokine release syndrome symptoms, the ATLCAR.CD19 cells have a safety switch that when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome to mild, but still allows the remaining iC9-CAR19 cells to effectively fight the leukemia. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable and and later to determine an optimal dose of AP1903 to be given to subjects to alleviate severe cytokine release syndrome.

Detailed Description

      STUDY OBJECTIVES

      Primary Objective

        -  To determine the safety and tolerability of autologous iC9-CAR19 T cells administered to
           adult and pediatric subjects with relapsed or refractory CD19+ Acute Lymphoblastic
           Leukemia (ALL).

      Secondary Objectives

        -  To identity a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and
           pediatric subjects with relapsed or refractory CD19+ ALL.

        -  To measure the survival of iC9-CAR19 T cells in vivo.

        -  To determine the anti-leukemia overall response rate (ORR) mediated by autologous
           iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or
           refractory CD19+ ALL.

        -  To determine overall survival (OS) in adult and pediatric subjects with relapsed or
           refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

        -  To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or
           refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

        -  To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed
           or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

        -  To measure patient-reported symptom, physical function, and health-related quality of
           life at baseline and over time in adult subjects treated with iC9-CAR19 T cells.

      ENDPOINTS

      Primary Endpoint

      Toxicity will be classified and graded according to the National Cancer Institute's Common
      Terminology Criteria for Adverse Events (CTCAE, version 5), CAR-T-cell-related encephalopathy
      (CRES) symptoms will be graded according to CRES Grading and CRS symptoms will be graded
      according to CRS Grading.

      (Note: The safety evaluation period for dose limiting toxicity assessment will encompass
      toxicities related to the cell therapy that are experienced starting on the day of iC9-CAR19
      T cell infusion up through 4 weeks post infusion. General safety monitoring will begin at the
      time of procurement).

      Secondary Endpoints

        -  The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose
           finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria,
           CRES grading criteria and CRS grading criteria

        -  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.

        -  Overall response rate (Complete Response (CR)/Complete Response with incomplete recovery
           of counts (CRi)) to iC9-CAR19 T cell therapy will be determined using National
           Comprehensive Cancer Network Response Criteria (NCCN) for ALL. Assessment of minimal
           residual disease (MRD) will be included as criterion of response (ie, the percentage of
           subjects who achieve CRm defined as MRD negative CR by either flow cytometry or PCR
           analysis will be determined).

        -  Overall survival will be measured from the date of administration of iC9-CAR19 T cells
           to the date of death.

        -  EFS applies to all subjects and will be measured from the date of administration of
           iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from
           CR or CRi, or death from any cause; subjects not known to have any of these events are
           censored on the date they were last examined.

        -  RFS will apply only to subjects achieving CR or CRi 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.

        -  Patient reported symptoms will be measured using selected symptoms from the NCI
           PRO-CTCAE. Patient-reported physical function will be measured using the PROMIS Physical
           Function Score derived from the PROMIS Physical Function Short Form 20a v1.0.
           Patient-reported health-related quality of life will be measured using the PROMIS Global
           Health Score derived from the PROMIS Global Health Short Form v1.0-1.1.

      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 low (CD3 count as assayed by flow cytometry less than
      200/μl) T-cell count in the peripheral blood, a leukopheresis may be performed to isolate
      sufficient T cells. The parameters for pheresis will be 2 blood volumes.

      iC9-CAR19 Cells Administration

      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. The starting dose of 5 x 10^5 transduced cells/kg (dose level 1) will enroll at
      least 3 adult subjects in the initial cohort. If there are no dose limiting toxicities within
      4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x 10^6
      transduced cells/kg in adults. If there is toxicity in 1/3 subjects in the initial cohort,
      the cohort will be expanded to enroll 3 more subjects. If dose level 1 is determined to be
      above a tolerable dose, de-escalation would occur to dose level -1 where subjects would
      receive 1 x 10^5 transduced cells/kg. The first subject enrolled on each dose level will be
      evaluated for a 4 week safety follow-up period prior to enrolling additional subjects on that
      dose level.

      Duration of Therapy

      Therapy in this study involves 1 infusion of iC9-CAR19 cells.

      Duration of Follow-up

      Subjects will be followed for up to 15 years for replication-competent retrovirus 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.
    

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
  • AP1903
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria - Cell Procurement:

          -  Written informed consent for procurement signed by subject or legal guardian of a
             pediatric subject and HIPAA authorization for release of personal health information.

          -  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.

          -  Relapsed or refractory precursor B cell ALL:

          -  Second 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 after 2 cycles of a standard of
             care chemotherapy regimen OR

          -  For adult subjects: first bone marrow relapse with duration of first CR <1 year OR
             first CR 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 relapses or primary refractory ALL
             are met and the biopsy for extramedullary disease confirms CD19 expression

          -  For pediatric subjects: first bone marrow or isolated non-CNS extramedullary relapse
             refractory to 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 with Ph+ ALL will be eligible if they have failed ≥ 2 ABL tyrosine kinase
             inhibitors. Subjects with the T315I ABL kinase point mutation will be eligible if they
             have failed ponatinib-containing therapy, regardless of the number of prior ABL
             tyrosine kinase inhibitors.

          -  CD19 positivity of lymphoblasts confirmed by flow cytometry or immunohistochemistry
             per institutional standards.

          -  Life expectancy ≥ 12 weeks.

          -  Demonstrate adequate renal and hepatic function as defined in the table below; all
             screening labs to be obtained within 72 hrs prior to procurement.

               -  Serum Creatinine: ≤ 1.5 x ULN

               -  Bilirubin: ≤ 1.5 x upper limit of normal (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 is defined below:

        Age Maximum Serum Creatinine (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 must have a negative serum pregnancy test within 72
             hours prior to procurement.

          -  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 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.

          -  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 chemotherapy are defined as methotrexate ≤30
             mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days.
             Corticosteroid-containing maintenance therapy is permitted only if corticosteroids are
             administered >14 days prior to procurement.

        Exclusion Criteria - Cell Procurement:

          -  Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing who cannot
             safely delay definitive treatment for their ALL by at least 4 weeks in the opinion of
             the investigator.

          -  Lumbar puncture must be performed prior to procurement and subjects with evidence of
             CNS3 disease will be excluded from study entry. Subjects with concurrent CNS3 disease
             and bone marrow relapse who have responded to CNS-directed therapy prior to
             enrollment/lymphodepletion will be allowed to participate. 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.

          -  Pregnant or breastfeeding.

          -  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 five 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.

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

          -  Patients with the following systemic viral infections will be excluded: active HIV,
             HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those
             samples confirming lack of active infection will be used to generate transduced cells)
             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 Hepatitis B surface antigen, or negative for HCV antibody or HCV viral
             load.

          -  Patients who are on treatment for other active uncontrolled infections (not referenced
             above) 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 ≥10mg/day
             prednisone or its equivalent; those receiving <10mg/day may be enrolled at discretion
             of investigator. 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 the procurement inclusion criteria within 2 weeks of
             procurement.

        Inclusion Criteria - Lymphodepletion

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

          -  Karnofsky score > 60% if ≥16 years old or Lansky performance score of greater than 60%
             if <16 years old

          -  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 in the table below; all
             screening labs to be obtained within 72 hrs prior to lymphodepletion.

               -  Serum Creatinine: ≤ 1.5 x ULN

               -  Bilirubin: ≤ 1.5 x upper limit of normal (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 is defined below:

        Age Maximum Serum Creatinine (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 must have a negative serum pregnancy test within 72
             hours prior to 72 hours prior to lymphodepletion.

          -  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 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.

          -  Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the
             need for intrathecal prophylaxis prior to lymphodepletion is left to the discretion of
             the investigator. Maintenance chemotherapy is defined as methotrexate ≤30 mg/m2/week,
             mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. For subjects who receive
             chemotherapy, including intrathecal chemotherapy, that does not fit this definition of
             maintenance chemotherapy, a two week washout between the last dose of standard of care
             chemotherapy and the beginning of lymphodepletion will be required.

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

        Exclusion Criteria- Lymphodepletion

          -  Pregnant or breastfeeding.

          -  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 five 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 (ie, two weeks) prior to
             lymphodepletionn or has received any tumor vaccines within the previous five weeks
             prior to lymphodepletion.

          -  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 Hepatitis B surface antigen, or negative for HCV antibody or
             HCV viral load.

          -  Patients who are on treatment for other active uncontrolled infections (not referenced
             above) 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 ≥10mg/day prednisone or its equivalent; those
             receiving <10mg/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 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.

        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 lymphodepletion
             may prompt exclusion from cell infusion at the discretion of the investigator.
      
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 (CTCAE, version 5.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. CAR-T-cell-related encephalopathy (CRES) symptoms will be graded according to the criteria outline in Section 12.6 CRES Grading in the protocol and CRS symptoms will be graded according to criteria outlined in Section 12.2 CRS Grading of the protocol.

Secondary Outcome Measures

Measure:Identify recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL.
Time Frame:4 weeks
Safety Issue:
Description:The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria and CRS grading criteria outlined in Section 12.2 Appendix B: CRS Grading Criteria and Management Guideline. CRES grading criteria outlined in section 12.6 of the protocol.
Measure:Measure the survival of iC9-CAR19 T cells in vivo as assessed by quantitative polymerase chain reaction (PCR) and flow cytometry.
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:Determine the 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 iC9-CAR19 T cells to the date of death.
Measure:Determine the Overall Response Rate (ORR) (Complete Response/Complete Response with incomplete recovery of counts) mediated by iC9-CAR19 T cell therapy using National Comprehensive Cancer Network Response Criteria (NCCN) for ALL.
Time Frame:15 years
Safety Issue:
Description:ORR (Complete Response/Complete Response with incomplete recovery of counts) to 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:Determine the event-free survival rate by measuring from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure, relapse or death.
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 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:Determine the relapse-free survival rate by measuring from the date of achievement of a remission until the date of relapse or death from any cause.
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:Measure the 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:Measure the patient reported physical functions in adult patients using PROMIS Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0.
Time Frame:15 years
Safety Issue:
Description:PROMIS (Patient-Reported Outcomes Measurement Information System) 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
Measure:Patient reported health-related quality of life in adult patients using the PROMIS Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1.
Time Frame:15 years
Safety Issue:
Description:PROMIS (Patient-Reported Outcomes Measurement Information System) 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

Details

Phase:Phase 1
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

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