Clinical Trials /

CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies

NCT04186520

Description:

This is a Phase I/II, interventional, single-arm, open-label, treatment study designed to evaluate the safety and efficacy of Interleukin-7 and Interleukin-15 (IL-7/IL-15) manufactured chimeric antigen receptor (CAR)-20/19-T cells as well as the feasibility of a flexible manufacturing schema in adult patients with B cell malignancies that have failed prior therapies.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies
  • Official Title: Phase I/II Study of Tandem, Bispecific Anti-CD19 Anti-CD20 CAR-T Cells for Patients With Relapsed and/or Refractory B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: IIT-SHAH-IL7-IL15-CD20-19
  • NCT ID: NCT04186520

Conditions

  • Non Hodgkin Lymphoma (NHL)
  • Mantle Cell Lymphoma (MCL)

Interventions

DrugSynonymsArms
8-Day Production of Car-T Cells8-Day Production of Car-T Cells
12-Day Production of Car-T Cells12-Day Production of Car-T Cells

Purpose

This is a Phase I/II, interventional, single-arm, open-label, treatment study designed to evaluate the safety and efficacy of Interleukin-7 and Interleukin-15 (IL-7/IL-15) manufactured chimeric antigen receptor (CAR)-20/19-T cells as well as the feasibility of a flexible manufacturing schema in adult patients with B cell malignancies that have failed prior therapies.

Detailed Description

      This is a Phase 1/Phase 2 study. The objectives are as follows:

        1. Phase 1/1b: Determine the safety of a fixed dose of 2.5 x 10^6 CAR-20/19-T cells/kg
           expanded with IL-7/IL-15 at 8 and 12-day manufacturing times in relapsed refractory
           B-cell non-Hodgkin lymphoma (NHL) followed by expansion cohorts.

        2. Phase 2:

             1. Determine the three-month complete response (CR) rate of CAR-20/19-T cells in
                Mantle Cell Lymphoma (MCL).

             2. Determine the feasibility of a flexible manufacturing process of CAR-20/19-T cells
                from patient apheresis products using the CliniMACS® Prodigy Cell processing
                device.
    

Trial Arms

NameTypeDescriptionInterventions
8-Day Production of Car-T CellsExperimentalPhase 1: Determine safety of 2.5x10^6 cells/kg IL-7/IL-15 expanded CAR-20/19-T cells in patients with relapsed, refractory B-cell NHL. Patients will be enrolled in 3+3 fashion. Phase 1b: Six to nine patient expansion cohorts at eight- and 12-day manufacturing. If six patients are enrolled in Phase 1 then only six additional patients will be added. If three patients are enrolled in Phase 1 then nine additional patients will be treated for a total of 12 in each group.
  • 8-Day Production of Car-T Cells
12-Day Production of Car-T CellsExperimentalPhase 1: Determine safety of 2.5x10^6 cells/kg IL-7/IL-15 expanded CAR-20/19-T cells in patients with relapsed, refractory B-cell NHL. Patients will be enrolled in 3+3 fashion. Phase 1b: Six to nine patient expansion cohorts at eight- and 12-day manufacturing. If six patients are enrolled in Phase 1 then only six additional patients will be added. If three patients are enrolled in Phase 1 then nine additional patients will be treated for a total of 12 in each group.
  • 12-Day Production of Car-T Cells
Phase 2 - Efficacy of CAR-20/19-T cells in MCLExperimentalSingle-stage Phase II design with 3-month CR as the target endpoint. Optimal production times will be determined following phase 1 of the study.
  • 8-Day Production of Car-T Cells
  • 12-Day Production of Car-T Cells

Eligibility Criteria

        GENERAL INCLUSION CRITERIA FOR ALL PATIENTS

          1. Patients must be aged ≥18 years with relapsed or refractory B-cell non-Hodgkin
             Lymphoma.

          2. Absolute cluster of differentiation 3 (CD3) count ≥50 mm3.

          3. Magnetic resonance imaging (MRI) brain and Lumbar Puncture with cerebrospinal fluid
             (CSF) analysis by cytology and flow cytometry without evidence of central nervous
             system (CNS) involvement ONLY in patients with history of CNS involvement or clinical
             suspicion at the time of enrollment.

          4. Measurable disease must be documented within four weeks of the time of consent defined
             as nodal lesions greater than 20 mm in the long axis or extranodal lesions >10 mm in
             long and short axis OR bone marrow involvement that is biopsy proven.

          5. Karnofsky performance score ≥60.

          6. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) <5 x upper limit of normal (ULN); serum bilirubin and alkaline
             phosphatase <5 x ULN, or considered not clinically significant as per the clinical PIs
             discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to
             underlying disease.

          7. Adequate renal function, defined as creatinine clearance>40 ml/min.

          8. Able to provide written informed consent.

          9. Agree to practice birth control during the study.

         10. Adequate cardiac function as indicated by New York Heart Association (NYHA)
             classification I or II AND left ventricular ejection fraction of ≥35% (by cardiac
             echocardiogram (ECHO) or multigated acquisition scan (MUGA)) and adequate pulmonary
             function as indicated by room air oxygen saturation of ≥92%.

         11. Expected survival >12 weeks.

         12. Negative urine or serum pregnancy test in females of child bearing potential at study
             entry.

         13. Meet criteria for regarding fertility and contraception.

         14. No contraindication to central line access.

        Phase 1: 3+3 COHORT ELEGIBILITY CRITERIA

          1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma
             (splenic, nodal, extranodal), Mantle Cell Lymphoma, and Diffuse large B-cell lymphoma
             (DLBCL) with associated subtypes (aggressive B-cell lymphoma, T-cell/histocyte rich
             B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive
             (EBV+) diffuse large B-cell lymphoma, transformed lymphoma such as transformed
             follicular or marginal zone, and Richter's transformation).

          2. Patients must have active, measurable disease as defined and meet one of the following
             criteria.

               1. Must have received Rituximab or another cluster of differentiation 20 (CD20)
                  antibody and at minimum two different chemotherapy regimens appropriate for their
                  disease and be ineligible to receive autologous transplant.

               2. Relapse post-autologous transplant

               3. Relapse post-allogeneic transplant

               4. Patients not previously treated with CAR-T cell therapy

        PHASE 1b and 2 COHORT ELEGIBILITY CRITERIA

        COHORT 1: 6-9 patient expansion with 8-day manufacturing (Phase 1b)

          1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma
             (splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell
             lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma,
             EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed
             follicular or marginal zone, and Richter's transformation).

          2. Patients must have active, measurable disease as defined and meet one of the following
             criteria:

               1. Must have received Rituximab or another cluster of differentiation 20 (CD20)
                  antibody and at minimum two different chemotherapy regimens appropriate for their
                  disease and be ineligible to receive autologous transplant.

               2. Relapse post-autologous transplant.

               3. Relapse post-allogeneic transplant.

               4. Relapse post-anti-cluster of differentiation 19 (CD19) CAR-T cell therapy.

             i. A maximum of 2 patients with prior CAR-T will be allowed in this cohort.

             COHORT 2: 6-9 patient expansion with 12-day manufacturing (Phase 1b)

        1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic,
        nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell lymphoma,
        T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse
        large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal
        zone, and Richter's transformation).

        2. Patients must have active, measurable disease as defined and meet one of the following
        criteria:

          1. Must have received Rituximab or another CD20 antibody and at minimum two different
             chemotherapy regimens appropriate for their disease and be ineligible to receive
             autologous transplant.

          2. Relapse post-autologous transplant.

          3. Relapse post-allogeneic transplant.

          4. Relapse post-anti-CD19 CAR-T cell therapy.

        i. A maximum of 2 patients with prior CAR-T will be allowed in this cohort.

        COHORT 3: Mantle Cell Lymphoma (Phase 2) 1. Diagnosis of Mantle Cell Lymphoma. 2. Patients
        must have active, measurable disease as previously designed and have relapsed, refractory
        disease as defined as one of the following:

          1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of
             anti-CD20 antibody.

          2. Progressive disease after ≥second line Bruton tyrosine kinase (BTK) inhibitor.

          3. Relapse post-autologous transplant.

          4. Relapse post-allogeneic transplant.

          5. Relapse post anti-CD19 CAR-T cell therapy.

        i. A maximum of four patients with history of prior anti-CD19 CAR-T will be allowed in this
        cohort.

        Exclusion Criteria (all patients) A potential subject who meets any of the following
        exclusion criteria is ineligible to participate in the study.

          1. Positive beta-human chorionic gonadotropin (HCG) in female of child-bearing potential
             defined as per table 1.

          2. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.

          3. History of significant autoimmune disease OR active, uncontrolled autoimmune
             phenomenon requiring steroid therapy defined as >20 mg of prednisone or equivalent
             daily.

          4. Presence of ≥grade 3 non-hematologic toxicities as per Common Terminology Criteria for
             Adverse Events (CTCAE) version 5.0 from any previous treatment unless it is felt to be
             due to underlying disease.

          5. Concurrent use of investigational therapeutic agents or enrollment on another
             therapeutic clinical trial at any institution. Minimum of ≥4 weeks required from
             administration of any other investigational agents on other clinical trials prior to
             enrollment on this CAR-T protocol.

          6. Refusal to participate in the long-term follow-up protocol.

          7. Patients with active CNS involvement by malignancy on magnetic resonance imaging (MRI)
             or by lumbar puncture.

             a. Patients with prior CNS disease that has been effectively treated will be eligible
             providing treatment was >4 weeks before enrollment and a remission documented within 8
             weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.

          8. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are
             excluded if they are <100 days' post-transplant, have evidence of active
             graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.

          9. Previous recipients of CAR-T cell therapy directed at either CD19 or CD20 are excluded
             if they are <100 days post prior CAR-T cell treatment (does not include
             re-enrollment).

             a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy
             post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by
             immunohistochemistry or flow cytometry.

         10. Anti-CD20 antibody treatment within 4 weeks of cell infusion.

         11. Anti-CD19 antibody treatment within 4 weeks of cell infusion.

         12. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell
             infusion (corticosteroids or targeted therapies for bridging allowable e.g.
             venetoclax, BTK inhibitors, lenalidomide, etc).

         13. Cytotoxic chemotherapy treatment within 10 days or steroid treatment (other than
             replacement dose steroids) within 7 days prior to apheresis collection for CAR-T
             cells.

         14. Patients post solid organ transplant who develop high grade lymphomas or leukemias.

         15. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Adverse Events after CAR 20/19-T cell infusion
Time Frame:Within the first 28 days after infusion
Safety Issue:
Description:Incidence of adverse events using NCI CTCAE version 5.0.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Medical College of Wisconsin

Last Updated

February 18, 2020