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A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

NCT02028455

Description:

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.

Related Conditions:
  • Acute Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia
  • Official Title: Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02: A Phase 1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia

Clinical Trial IDs

  • ORG STUDY ID: PLAT-02
  • NCT ID: NCT02028455

Conditions

  • CD19+ Acute Leukemia

Interventions

DrugSynonymsArms
Patient Derived CD19 specific CAR T cells also expressing an EGFRtCohort 1

Purpose

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.

Detailed Description

      Upon meeting the eligibility requirements and enrolling on study, subjects will undergo
      apheresis to obtain the T cells for the generation of the CD19 CAR+ T cells. In patients with
      a prior history of allogeneic HCT, the T cells obtained are of donor origin. The T cells are
      isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown
      separately, transduced with a lentivirus to express the CD19 CAR as well as a truncated EGFR
      that has no signaling capacity (noted EGFRt) and expanded in culture over a three week
      period. During the process of cell generation, subjects will continue to be cared for by
      their primary oncologist and may undergo additional treatment directed at the leukemia during
      this time.

      After the CAR+ T cells have been generated, the subject undergoes a disease assessment and
      determination if lymphodepletion is necessary. A variety of lymphodepletion strategies are
      acceptable and determined on a case by case basis. At least 48 hours after the completion of
      lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1
      ratio of CD4 to CD8 CAR+ T cells.

      Following treatment with the CAR+ T cells, subjects will be followed intensely for 2 months
      with serial blood testing and re-evaluation of disease status with bone marrow aspirates.
      After 2 months, the subjects clinical care will be resumed by their primary oncologist, and
      it is possible that they would receive additional chemotherapy or HCT.

      Some subjects will receive cetuximab for ablation of the genetically modified T cells.
      Criteria to receive cetuximab include acute toxicities that are life threatening, as well as
      an ongoing remission with continued B cell aplasia.

      Upon completion of the study, subjects will be followed bi-annually for 5 years, and then
      annually for 10 additional years with either a medical history, physical exam and blood tests
      or a phone call/questionnaire. This follow up will help to determine if the subject develops
      any long-term health problems related to the CAR+ T cells including a new cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalThis cohort will determine the maximum tolerated dose of the Patient Derived CD19 specific CAR T cells also expressing an EGFRt and is restricted to patients with a prior history of allo-HCT
  • Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Cohort 2AExperimentalThis cohort is for patient who have a history of allo-HCT with recurrence of disease post HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1.
  • Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Cohort 2BExperimentalThis cohort is restricted to patients wtih no prior history of allo-HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1
  • Patient Derived CD19 specific CAR T cells also expressing an EGFRt

Eligibility Criteria

        Inclusion Criteria:

        Patients must be ≥12 months of age and <27 years of age at the time of study enrollment.

        Must be ≥10kg

        Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated
        extramedullary disease following allogeneic HCT.

        OR

        No prior history of allogeneic HCT (one of the following)

          -  2nd or greater relapse, with or without extramedullary disease (isolated
             extramedullary disease is eligible)

          -  1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast
             disease, with or without extramedullary disease

          -  Primary Refractory as defined as having M2 or M3 marrow after induction

          -  Subject has indication for HCT but has been deemed ineligible

        OR

        CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies
        available

        Patients with CNS involvement are eligible provided that they are asymptomatic and in the
        opinion of the study PI have a reasonable expectation that disease burden can be controlled
        in the interval between enrollment and T cell infusion. Patients that have a significant
        neurologic deterioration will be not be eligible for T cell infusion until alternate
        therapies result in neurological stabilization.

        Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50
        for patients ≥16 years of age.

        Life Expectancy of >8 weeks

        Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks
        prior to enrollment.

        Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or
        radiotherapy

        It must be at least 7 days since last chemotherapy was administered (this does not include
        intrathecal chemotherapy or maintenance chemotherapy)

        No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of
        enrollment.

        No prior genetically modified cell therapy that is still detectable or virotherapy allowed.

          -  Normal serum creatinine based on age/gender

          -  Total bilirubin </3x ULN OR conjugated bilirubin </2mg/dl

          -  ALT </5X ULN

          -  SF of >28% by ECHO or EF >50% by MUGA

          -  ALC of >/= 100 cells/ul

          -  Pulse ox >/= 90% on room air

        Patient must have documented negative HIV antigen and antibody, Hepatitis B surface
        antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with
        positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible.

        Patients must NOT have active clinically significant CNS dysfunction (including but not
        limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular
        ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain
        syndrome, psychosis, coordination or movement disorder)

        Must agree to highly effective contraception during and for 12 months after T cell
        infusion.

        Patients must be able to tolerate apheresis procedure, including placement of temporary
        apheresis line if required.

        Patients must NOT have an active malignancy other than CD19+ leukemia.

        Patients must NOT have an active severe infection defined as:

          -  A positive blood culture within 48 hours of study enrollment

          -  A fever above 38.2 C AND clinical signs of infection within 48 hours of study
             enrollment

        Patients must NOT have any concurrent medical condition that, in the opinion of the PI or
        designee, would prevent the patient from undergoing protocol-based therapy. Patients with a
        primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial.

        Research participant or parent/legal guardian must agree to participate in long-term
        follow-up for up to 15 years, if they are enrolled in the study and receive T-cell
        infusion.
      
Maximum Eligible Age:26 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Adverse Events
Time Frame:30 days
Safety Issue:
Description:The safety of the T cell infusion will be described and the maximum tolerated dose determined

Secondary Outcome Measures

Measure:Persistence of functional CD19 CAR+ T cells
Time Frame:63 days
Safety Issue:
Description:Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood, bone marrow and CSF
Measure:Number of participants with recrudescence or development of acute GVHD
Time Frame:63 days
Safety Issue:
Description:
Measure:Number of participants who have T cells ablated with cetuximab
Time Frame:3 years
Safety Issue:
Description:The efficacy of cetuximab to ablate the T cells will be measured by loss of detection of T cells and any associated toxicities as well as facilitating B cell recovery.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seattle Children's Hospital

Trial Keywords

  • pediatric
  • young adult
  • acute lymphoblastic leukemia
  • CD19
  • leukemia
  • Chimeric Antigen Receptor
  • T cell

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