Clinical Trials /

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

NCT03019055

Description:

This is a phase 1/1b, interventional single arm, open label, treatment study designed to evaluate the safety and feasibility of infusion of autologous T cells engineered to contain an anti-CD19 and anti-CD20 scFv coupled to CD3ζ and 4-1BB signaling domains in patients with relapsed and/or refractory CD19 or CD20 positive B cell malignancies

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell
  • Official Title: Phase 1/1b Study of Redirected Autologous T Cells Engineered to Contain an Anti CD19 and Anti CD20 scFv Coupled to CD3ζ and 4-1BB Signaling Domains in Patients With Relapsed and/or Refractory CD19 or CD20 Positive B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: PRO00028724
  • NCT ID: NCT03019055

Conditions

  • CLL/SLL
  • Lymphomas Non-Hodgkin's B-Cell

Interventions

DrugSynonymsArms
CAR-20/19-TCAR-20/19-T cells

Purpose

This is a phase 1/1b, interventional single arm, open label, treatment study designed to evaluate the safety and feasibility of infusion of autologous T cells engineered to contain an anti-CD19 and anti-CD20 scFv coupled to CD3ζ and 4-1BB signaling domains in patients with relapsed and/or refractory CD19 or CD20 positive B cell malignancies

Detailed Description

      This is a single center, single arm, open label phase I/1b study to demonstrate the
      feasibility of manufacturing CAR-T cells expressing tandem receptors against both CD20 and
      CD19 (CAR-20/19-T) in a completely closed system using the CliniMACS Prodigy device and then
      determine the safety of this dual targeted CAR in a first-in-human study of patients with
      relapsed and refractory B cell malignancies. Secondary outcomes will include response rates,
      and observed toxicities of the treatment, specifically the development of cytokine release
      syndrome (CRS), an inflammatory storm that has been seen with previous CAR-T therapies.
    

Trial Arms

NameTypeDescriptionInterventions
CAR-20/19-T cellsExperimentalDose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1
  • CAR-20/19-T

Eligibility Criteria

        Inclusion Criteria

          1. Diagnosis of B-cell NHL or CLL/SLL: Patients must be aged≥18 years with relapsed,
             refractory disease and no available curative options that meet clinical criteria to
             initiate treatment.

          2. Patients with B-cell NHL or CLL/SLL must have either CD19 or CD20 positive disease on
             most recent biopsy performed (a repeat biopsy is not mandatory for this study except
             as noted below). A minimum of 5% CD19 or CD20 positivity by immunohistochemistry or
             flow cytometry on prior or repeat biopsy is required.

          3. Absolute CD3+ T cell count ≥50/mm3.

          4. MRI brain and Lumbar Puncture with CSF analysis by cytology and flow cytometry without
             evidence of CNS involvement ONLY in patients with history of CNS involvement.

          5. Measurable disease must have been documented within 4 weeks of the time of consent
             defined as the following by disease specific subtype:

               1. B-cell NHL: Active disease 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.

               2. CLL/SLL: Active disease by either bone marrow, peripheral flow cytometry, or CT
                  and/or PET imaging with nodal disease.

          6. Patients should have failed at least two lines of a standard treatment and meet
             disease specific criteria detailed below:

               1. CLL/SLL: measurable disease as defined above that has relapsed after at least one
                  line of chemo-immunotherapy and progressed or intolerant to ibrutinib
                  monotherapy.

               2. CD19 or CD20 positive B cell NHL limited to the following histologies: Advanced
                  Stage III or IV Follicular Lymphoma, Diffuse Large B cell Lymphoma and associated
                  subtypes (e.g. 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 lymphoma,
                  and Richter's transformation) and Mantle cell lymphoma. Specific criteria
                  include:

                    -  Patients must have active, measurable disease after two lines of cytotoxic
                       chemotherapy of which one must be anthracycline containing.

                    -  Must have received Rituximab or another CD20 antibody and at minimum two
                       chemotherapy regimens appropriate for their disease.

                    -  Either failed autologous transplant or ineligible to receive autologous
                       transplant

          7. Karnofsky performance score ≥70. See Appendix A for scales.

          8. Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30.

          9. Adequate hepatic function, defined as AST and 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.

         10. Adequate renal function, defined as creatinine clearance>60 ml/min

         11. Able to provide written informed consent.

         12. Agree to practice birth control during the study.

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

         14. Expected survival >12 weeks.

         15. Negative urine or serum pregnancy test in females of child bearing potential at study
             entry and again within 48 hours' prior lymphodepleting chemotherapy.

         16. Patients with prior blinatumomab treatment require repeat biopsy post-blinatumomab
             treatment that demonstrates CD19 or CD20 positive disease.

         17. Meet criteria for regarding fertility and contraception.

         18. Central line access will be required for CAR-20/19-T cell infusion.

        Exclusion Criteria

          1. Positive beta-HCG in female of child-bearing potential.

          2. Patients with known systemic allergy to bovine or murine products.

          3. Known prior positive serology for human anti-mouse antibody (HAMA).

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

          5. History of significant autoimmune disease OR active, uncontrolled autoimmune
             phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis,
             autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring
             steroid therapy defined as >20 mg of prednisone or equivalent daily.

          6. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any
             previous treatment unless it is felt to be due to underlying disease.

          7. 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.

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

          9. Patients with active CNS involvement by malignancy on 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.

         10. 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.

         11. Previous CAR-T cell therapy directed at either CD19 or CD20 within 100 days of planned
             CAR-20/19-T cell infusion (does not include re-enrollment)

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

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

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

         14. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell
             infusion.

         15. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than
             replacement dose steroids) within 7 days prior to apheresis collection for CAR-T
             cells.

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

         17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.

        Special Criteria for regarding Fertility and Contraception

        Female subjects of reproductive potential (women who have reached menarche or women who
        have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses
        within the preceding 24 months, or have not undergone a sterilization procedure
        [hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy
        test performed as part of eligibility criteria and again within 48 hours of initiation of
        lymphodepleting chemotherapy.

        Due to the high-risk level of this study, while enrolled, all subjects must agree not to
        participate in a conception process (e.g., active attempt to become pregnant or to
        impregnate, sperm donation, in vitro fertilization). Additionally, if participating in
        sexual activity that could lead to pregnancy, the study subject must agree to use reliable
        and double barrier methods of contraception during the follow-up period of the protocol.

        Acceptable birth control includes a combination of two of the following methods:

          -  Condoms* (male or female) with or without a spermicidal agent.

          -  Diaphragm or cervical cap with spermicide

          -  Intrauterine device (IUD)

          -  Hormonal-based contraception Subjects who are not of reproductive potential (women who
             are premenarche or have been post-menopausal for at least 24 consecutive months or
             have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral
             oophorectomy or men who have documented azoospermia) are eligible without requiring
             the use of contraception.
      
Maximum Eligible Age:70 Years
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:Determine the toxicity profile of CAR 20/19-T cell therapy

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medical College of Wisconsin

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