Clinical Trials /

CD19-Specific T Cells Post AlloSCT

NCT03579888

Description:

This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients 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 patient's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the patient's body. Receiving the T-cell infusion may help to control the disease.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • B-Cell Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Mantle Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Small Lymphocytic Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD19-Specific T Cells Post AlloSCT
  • Official Title: Donor-Derived Very-Rapid Manufactured CD19-Specific T Cells for Lymphoid Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2019-1063
  • SECONDARY ID: NCI-2020-03608
  • SECONDARY ID: 2019-1063
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03579888

Conditions

  • B Acute Lymphoblastic Leukemia With t(v;11q23.3); KMT2A Rearranged
  • Recurrent B Acute Lymphoblastic Leukemia
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Non-Hodgkin Lymphoma
  • Recurrent Ph-Like Acute Lymphoblastic Leukemia
  • Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory B Acute Lymphoblastic Leukemia
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Refractory Mantle Cell Lymphoma
  • Refractory Non-Hodgkin Lymphoma
  • Refractory Ph-Like Acute Lymphoblastic Leukemia
  • Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Refractory Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T CellsAutologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-EGFRt T Cells, CD19-CD8CD28zCAR-specific-mbIL15-HER1t T-lymphocytesTreatment (fludarabine, cyclophosphamide, CD19 T cell)
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (fludarabine, cyclophosphamide, CD19 T cell)
FludarabineFluradosaTreatment (fludarabine, cyclophosphamide, CD19 T cell)

Purpose

This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients 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 patient's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the patient's body. Receiving the T-cell infusion may help to control the disease.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the safety and maximum tolerated dose (MTD) of donor-derived genetically
      modified, CD19-specific T cells expressing mbIL15 and HER1t using the Rapid Personalized
      Manufacture (RPM) process (autologous CD19-CD8-CD28-CD3zeta-chimeric antigen receptor
      [CAR]-mbIL15-HER1t T cells [CD19-mbIL15-CAR-T cells]) administered to patients with CD19+
      advanced lymphoid malignancies who have previously received an allogeneic hematopoietic stem
      cell transplantation (HSCT), including haploidentical HSCT.

      SECONDARY OBJECTIVES:

      I. To demonstrate the feasibility of the RPM 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 demonstrate
      the homing ability of the infused T cells. VIII. To assess disease response after T-cell
      infusion. IX. To assess progression-free and overall survival. X. To detect emergence of CD19
      negative (neg) malignant B cells.

      OUTLINE: This is a dose-escalation study of autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t
      T cells.

      CHEMOTHERAPY: Patients 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: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells
      IV over 15-30 minutes on day 0.

      After completion of study treatment, patients are followed up within 3 days after T-cell
      infusion and at 1, 2, 3, 4, 6, and 8 weeks, then at 3, 6, and 12 months, then periodically
      for up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fludarabine, cyclophosphamide, CD19 T cell)ExperimentalCHEMOTHERAPY: Patients 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: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.
  • Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  RECIPIENT: Patients with high risk or relapsed disease who are planning to receive, or
             have received prior allogeneic HSCT from an human leukocyte antigen (HLA)-matched
             related, or HLA-mismatched related donor; high risk is defined as patients with acute
             lymphoblastic leukemia who have delayed clearance of minimal residual disease,
             Philadelphia (Ph)-like, or complex, 11q23 or hypodiploid karyotype

          -  RECIPIENT: Available donor who provided hematopoietic stem-cell (HSC)

          -  RECIPIENT: Patients with CD19+ lymphoid malignancies that are refractory to or
             intolerant of standard treatment (as defined below):

               -  B-cell Acute Lymphoblastic Leukemia (ALL)

               -  Non-Hodgkin lymphoma (NHL) to include diffuse large B-cell lymphoma (DLBCL) not
                  otherwise specified, primary mediastinal large B cell lymphoma, mantle cell
                  lymphoma, or transformed follicular lymphoma (TFL) as defined by the World Health
                  Organization 2008 criteria

               -  Small lymphocytic lymphoma (SLL)

               -  Chronic lymphocytic leukemia (CLL)

               -  NOTE: Refractory disease for acute and chronic leukemia is 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 extra-medullary disease to most
                       recent therapy

               -  NOTE: Refractory disease for lymphoma is defined as:

                    -  Progressive disease or stable disease lasting =< 6 months, as best response
                       to most recent chemotherapy regimen; or disease progression or recurrence =<
                       12 months after prior ASCT

                    -  Prior therapy must have included an anti-CD20 monoclonal antibody-containing
                       regimen and an anthracycline-containing chemotherapy regimen

                    -  For patients with TFL, prior chemotherapy for follicular lymphoma and
                       subsequent refractory disease after transformation to DLBCL

                    -  At least one measurable lesion according to revised International Working
                       Group (IWG) Response Criteria

          -  RECIPIENT: In patients with prior transplant, treatment will begin no earlier than 3
             months post-transplant. Enrollment can occur earlier to allow time for donor cell
             collection

          -  RECIPIENT: Karnofsky performance scale > 60

          -  RECIPIENT: Patient able to provide written informed consent

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

          -  RECIPIENT: Negative human anti-mouse antibody (HAMA)

          -  DONOR: HLA-matched related, HLA-mismatched related, including haploidentical donor, or
             related donor cleared to donate based on Stem Cell Transplantation and Cellular
             Therapy (SCTCT) standard-of-care (SOC) guidelines

          -  DONOR: Negative beta HCG in female of child-bearing potential defined as:

               -  Not post-menopausal for 12 months, or

               -  No previous surgical sterilization, or

               -  Lactating females

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Patient must have measurable disease at
             the time of treatment

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Not received anti-thymocyte globulin
             (ATG), Campath, or other T-cell immunosuppressive antibodies or donor-lymphocyte
             infusion in the 28 days prior to T-cell infusion

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x upper limit of
             normal (ULN)

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Alanine aminotransferase (ALT)/aspartate
             aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN if documented liver metastases

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Total bilirubin =< 1.5 mg/dL, except in
             patients with Gilbert's syndrome in whom total bilirubin must be =< 3.0 mg/dL

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Cardiac ejection fraction >= 40%, and no
             clinically-significant electrocardiogram (ECG) findings

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No clinically significant pleural
             effusion, baseline oxygen saturation > 90% on room air

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No evidence of grade >= 2 active graft
             versus host disease (GVHD) using the Center for International Blood and Marrow
             Transplant Research (CIBMTR) Acute GVHD Grading System or requiring systemic steroid
             therapy greater than physiologic dosing at time of starting treatment

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Non-hematologic toxicity grade >= 2
             (Common Terminology Criteria for Adverse Events [CTCAE] version 5) related to the
             lymphodepleting chemotherapy until the toxicity has resolved to grade =< 1 and the
             patient is afebrile

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No new grade > 2 neurologic, pulmonary,
             cardiac, gastrointestinal, renal or hepatic (excluding albumin) toxicity

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x ULN

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Oxygen saturation > 90% on room air

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Active clinically significant infection
             within 7-days of study treatment

          -  T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Using an investigational agent

        Exclusion Criteria:

          -  RECIPIENT: 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

          -  RECIPIENT: Patients with allergy to mouse products or cetuximab

          -  RECIPIENT: Active central nervous system (CNS) disease in patient with history of CNS
             malignancy

          -  RECIPIENT: Positive serology for human immunodeficiency virus (HIV)

          -  RECIPIENT: Active hepatitis B or active hepatitis C

          -  RECIPIENT: Has received a T-cell product within 6 weeks prior to planned infusion of
             genetically modified T cells
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Incidence and grading of cytokine release syndrome (CRS)
Time Frame:Up to 12 months
Safety Issue:
Description:Graded according to CTCAE.
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:Homing ability of the infused T cells
Time Frame:Up to 12 months
Safety Issue:
Description:Homing will be assessed based on presence of infused T cells within biopsied tissue. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.
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 will be computed along with a corresponding 95% confidence interval. 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
Time Frame:Up to 12 months
Safety Issue:
Description:Graded according to CTCAE.
Measure:Presence of CD19 negative (-) malignant B cells
Time Frame:Up to 12 months
Safety Issue:
Description:Presence of CD19- malignant B cells will be based on flow cytometry staining for CD19 in the context of staining for antigens to detect cancerous B cells. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.
Measure:Progression-free survival
Time Frame:From the time of T-cell infusion to date of progression of date of death, assessed up to 12 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and presented along with their 95% confidence intervals. Additional statistical analyses will be performed if deemed appropriate.
Measure:Overall survival
Time Frame:From the time of T-cell infusion to date of death, assessed up to 12 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and presented along with their 95% confidence intervals. Additional statistical analyses will be performed if deemed appropriate.

Details

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

Last Updated

July 2, 2020