Clinical Trials /

CD19+ Specific Chimeric Antigen Receptor T Cells in Treating Participants With CD19+ Lymphoid Malignancies

NCT03579888

Description:

This phase I trial studies the side effects and best dose of CD19 positive (+) specific chimeric antigen receptor T cells in treating participants with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a participant's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the body of the participant. The genetically modified CD19+ specific chimeric antigen receptor T cells may or may not be able to attack cancer cells in participants with CD19+ lymphoid malignancies.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia
  • Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD19+ Specific Chimeric Antigen Receptor T Cells in Treating Participants With CD19+ Lymphoid Malignancies
  • Official Title: Infusion of Minimally Expanded CD19+ Specific Chimeric Antigen Receptor T Cells for Patients With Advanced Lymphoid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2017-0908
  • SECONDARY ID: NCI-2018-01110
  • NCT ID: NCT03579888

Conditions

  • Acute Lymphoblastic Leukemia
  • Blasts More Than 5 Percent of Bone Marrow Nucleated Cells
  • Blasts More Than 5 Percent of Peripheral Blood White Cells
  • CD19 Positive
  • Chronic Lymphocytic Leukemia
  • Minimal Residual Disease
  • Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T CellsCD19-CD8CD28zCAR-specific-mbIL15-HER1t T-lymphocytes; Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-EGFRt T CellsTreatment (fludarabine, cyclophosphamide, T cell infusion)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (fludarabine, cyclophosphamide, T cell infusion)
FludarabineFluradosaTreatment (fludarabine, cyclophosphamide, T cell infusion)

Purpose

This phase I trial studies the side effects and best dose of CD19 positive (+) specific chimeric antigen receptor T cells in treating participants with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a participant's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the body of the participant. The genetically modified CD19+ specific chimeric antigen receptor T cells may or may not be able to attack cancer cells in participants with CD19+ lymphoid malignancies.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and maximum tolerated dose (MTD) of genetically modified,
      CD19-specific T cells expressing membrane-bound form of IL-15 (mbIL15) and HER1t manufactured
      under point of care (P-O-C) process (P-O-C CD19-mbIL15-chimeric antigen receptor [CAR]-T
      cells) administered into patients with CD19+ advanced lymphoid malignancies.

      SECONDARY OBJECTIVES:

      I. To describe the feasibility of the P-O-C process. II. To determine the incidence and
      grading of cytokine release syndrome (CRS) and neurotoxicity.

      III. To determine persistence of genetically modified T cells. IV. To determine if cetuximab
      can control numbers of infused T cells. V. To screen for the development of host immune
      responses against the transgenes (one or more of CAR, mbIL15, HER1t).

      VI. To determine cytokine profile of the patient with infused T cells. VII. To describe the
      homing ability of the infused T cells. VIII. To assess disease response at day 30 and day
      100. IX. To assess disease progression-free and overall survival. X. Emergence of CD19
      negative (neg) malignant B cells.

      OUTLINE: This is a dose-escalation study of CD19+ specific chimeric antigen receptor T cells.

      CHEMOTHERAPY: Participants receive fludarabine intravenously (IV) over 1 hour and
      cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression
      or unacceptable toxicity.

      T CELL INFUSION: Participants receive CD19+ specific chimeric antigen receptor T cells IV
      over 15-30 minutes on day 0 in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed for up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fludarabine, cyclophosphamide, T cell infusion)ExperimentalCHEMOTHERAPY: Participants receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity. T CELL INFUSION: Participants receive CD19+ specific chimeric antigen receptor T cells IV over 15-30 minutes on day 0 in the absence of disease progression or unacceptable toxicity.
  • Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a history of CD19+ lymphoid malignancy defined as acute lymphoblastic
             leukemia (ALL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or
             chronic lymphocytic leukemia (CLL) with active disease defined by presence of > 5%
             malignant blasts in bone marrow and/or peripheral blood, and/or minimal residual
             disease by flow cytometry or molecular analysis for fusion proteins, and/or positive
             imaging for extramedullary disease. Patients must have measurable disease at time of
             study treatment.

          -  Confirmed history of CD19-positivity by flow cytometry for malignant cells.

          -  Karnofsky performance scale > 70.

          -  Patient able to provide written informed consent.

          -  Patient able to provide written informed consent for the long-term follow-up (LTFU)
             gene therapy study.

          -  Absolute T-cell count (ATC) at screening >= 0.07 K/microL. This is defined as CD3+
             T-cell percent (expressed as fraction of 100%) multiplied by the absolute lymphocyte
             count (ALC, expressed in K/microL).

          -  Patients at least 3 weeks from last cytotoxic chemotherapy. Patients may continue
             tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior
             to administration of lymphodepleting chemotherapy.

          -  Creatinine clearance (as estimated by Cockcroft Gault) >= 50 cc/min.

          -  Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x upper limit
             of normal (ULN) or =< 5 x ULN if documented liver metastases.

          -  Total bilirubin =< 1.5 mg/dL, except in subjects with Gilbert's syndrome in whom total
             bilirubin must be =< 3.0 mg/dL.

          -  Cardiac ejection fraction >= 40%, and no clinically significant electrocardiogram
             (ECG) findings.

          -  No clinically significant pleural effusion, baseline oxygen saturation > 92% on room
             air.

          -  Negative human anti-mouse antibody (HAMA) result.

        Exclusion Criteria:

          -  Positive beta human chorionic gonadotropin (HCG) in female of child-bearing potential
             defined as not post-menopausal for 12 months or no previous surgical sterilization or
             lactating females.

          -  Patients with known allergy to bovine or murine products.

          -  Positive serology for human immunodeficiency virus (HIV).

          -  Active hepatitis B or active hepatitis C.

          -  Has received a T-cell product within 6 weeks prior to planned infusion of genetically
             modified T cells.

          -  Has received allogeneic hematopoietic cell transplantation (HSCT) within 3 months of
             planned infusion of genetically modified T cells; HSCT >= 3 months from CAR-T cell
             infusion eligible.

          -  History of allergic reactions to cetuximab.

          -  Active clinically significant infection within 7-days of study treatment.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 15 years
Safety Issue:
Description:Adverse events will be summarized by frequencies and percentages by dose level.

Secondary Outcome Measures

Measure:Incidence and grading of cytokine release syndrome (CRS) graded according to CTCAE
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Persistence of genetically modified T cells
Time Frame:Up to 12 months
Safety Issue:
Description:Persistence of genetically modified T cells will be assessed by the frequency of patients with any detectable CAR+ T cells.
Measure:Change in numbers of infused T cells
Time Frame:Up to 12 months
Safety Issue:
Description:For patients receiving cetuximab (i.e., those who experience >= grade 3 CRS), the change in infused CAR+ T cells from before cetuximab treatment to the nadir of CAR+ T cells after cetuximab summarized by mean, standard deviation, median, and range and days to achieve nadir.
Measure:Development of host immune responses against transgenes
Time Frame:Up to 12 months
Safety Issue:
Description:The development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t) may be assessed by the percentage of patients with antibody formation against each one of the transgenes.
Measure:Cytokine levels
Time Frame:Up to 12 months
Safety Issue:
Description:Individual patient and aggregate cytokine levels (e.g., IL-15, IL-12, IL-8, etc.) will be summarized by means, standard deviations, medians, and ranges.
Measure:Disease response
Time Frame:At days 30 and 100
Safety Issue:
Description:Percentage of patients experiencing disease response, defined as partial or complete clearance of disease e.g., by positron emission tomography (PET) and/or bone marrow report. Further, the percentage of responders with CD19+ lymphoma or leukemia will be reported. The percentage of patients who had T cells successfully prepared, released, and infused will be reported. Additional statistical analyses will be performed if deemed appropriate.
Measure:Neurotoxicity graded according to CTCAE
Time Frame:up to 12 months
Safety Issue:
Description:
Measure:Persistence of genetically modified T cells
Time Frame:up to 12 months
Safety Issue:
Description:Persistence of genetically modified T cells will be assessed by the percentage of patients with any detectable CAR+ T cells.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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