Clinical Trials /

CD19 Chimeric Antigen Receptor (CAR) T Cells for Adults With Recurrent or Refractory B Cell Malignancies

NCT04214886

Description:

In this protocol, the investigators hypothesize that modifying the process of producing CAR+ T-cells can help to improve responses and reduce toxicities. Building on previous in vitro studies that have shown successful production of CAR+ T-cells using a new production approach, the investigators are now studying the ability to produce these CAR+ T-cells and determine how well they work in the clinical setting.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD19 Chimeric Antigen Receptor (CAR) T Cells for Adults With Recurrent or Refractory B Cell Malignancies
  • Official Title: Dose Escalation Study of CD19 Chimeric Antigen Receptor (CAR) T Cells With a CD34 Selection Marker in Adults With Recurrent or Refractory B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 212594
  • NCT ID: NCT04214886

Conditions

  • B-Cell Acute Lymphoblastic Leukemia, Adult
  • B-cell Lymphoma Refractory
  • B-cell Lymphoma Recurrent

Interventions

DrugSynonymsArms
FludarabineCAR 5 x 105 transduced T cells/kg (Dose Level -1)
CyclophosphamideCAR 5 x 105 transduced T cells/kg (Dose Level -1)
CD19-CD34 CAR transduced T cellsCAR 5 x 105 transduced T cells/kg (Dose Level -1)

Purpose

In this protocol, the investigators hypothesize that modifying the process of producing CAR+ T-cells can help to improve responses and reduce toxicities. Building on previous in vitro studies that have shown successful production of CAR+ T-cells using a new production approach, the investigators are now studying the ability to produce these CAR+ T-cells and determine how well they work in the clinical setting.

Detailed Description

      Autologous peripheral blood mononuclear cell (PBMC) will be obtained by leukapheresis over
      one day and the cells will be transduced with an in house designed CAR retroviral vector.
      Participants will receive daily intravenous (IV) infusion of lymphodepleting regimen of
      fludarabine and cyclophosphamide for total of 3 days (Days -5, -4, -3). The dose of
      cyclophosphamide will be given at 500mg/m2. The dose of fludarabine will be given at 30mg/m2.
      Participants will receive the CAR transduced T cells IV infusion in the BMT Inpatient Unit
      and remain admitted for close monitoring for at least the first 7 days following the cell
      infusion (D0 to Day +7), possibly longer if any side effects are encountered. The CAR
      transduced T cells will be escalated from 1 x 106 transduced T cells/kg (± 20%) to 2 x 106
      transduced T cells/kg (± 20%) in a Phase I design, based on toxicity. Once discharged from
      the inpatient unit, for the next 7 days (Day +8 to Day +14) the patients will be evaluated in
      the High Dose Unit (labs and physical exam) to screen for toxicities.
    

Trial Arms

NameTypeDescriptionInterventions
CAR 5 x 105 transduced T cells/kg (Dose Level -1)ExperimentalAutologous peripheral blood mononuclear cell (PBMC) will be obtained by leukapheresis over one day. Daily intravenous (IV) infusion of fludarabine and cyclophosphamide for total of 3 days (Days -5, -4, -3). The dose of cyclophosphamide will be given at 500mg/m2. The dose of fludarabine will be given at 30mg/m2. CD19-CD34 CAR transduced T cells will be administered IV at a dose level of 5 x 105 transduced T cells/kg.
  • Fludarabine
  • Cyclophosphamide
  • CD19-CD34 CAR transduced T cells
CAR 1 x 106 transduced T cells/kg (Dose Level 1)ExperimentalAutologous peripheral blood mononuclear cell (PBMC) will be obtained by leukapheresis over one day. Daily intravenous (IV) infusion of fludarabine and cyclophosphamide for total of 3 days (Days -5, -4, -3). The dose of cyclophosphamide will be given at 500mg/m2. The dose of fludarabine will be given at 30mg/m2. CD19-CD34 CAR transduced T cells will be administered IV at a dose level of 1 x 106 transduced T cells/kg.
  • Fludarabine
  • Cyclophosphamide
  • CD19-CD34 CAR transduced T cells
CAR 1.5 x 106 transduced T cells/kg (Dose Level 2)ExperimentalAutologous peripheral blood mononuclear cell (PBMC) will be obtained by leukapheresis over one day. Daily intravenous (IV) infusion of fludarabine and cyclophosphamide for total of 3 days (Days -5, -4, -3). The dose of cyclophosphamide will be given at 500mg/m2. The dose of fludarabine will be given at 30mg/m2. CD19-CD34 CAR transduced T cells will be administered IV at a dose level of 1.5 x 106 transduced T cells/kg.
  • Fludarabine
  • Cyclophosphamide
  • CD19-CD34 CAR transduced T cells
CAR 2 x 106 transduced T cells/kg (Dose Level 3)ExperimentalAutologous peripheral blood mononuclear cell (PBMC) will be obtained by leukapheresis over one day. Daily intravenous (IV) infusion of fludarabine and cyclophosphamide for total of 3 days (Days -5, -4, -3). The dose of cyclophosphamide will be given at 500mg/m2. The dose of fludarabine will be given at 30mg/m2. CD19-CD34 CAR transduced T cells will be administered IV at a dose level of 2 x 106 transduced T cells/kg.
  • Fludarabine
  • Cyclophosphamide
  • CD19-CD34 CAR transduced T cells

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must be greater than or equal to 18 years of age.

          -  Participants must have Eastern cooperative oncology group (ECOG) performance status of
             0 or 1, or Karnofsky greater than or equal to 80%

          -  Participants must have been diagnosed with histologically confirmed aggressive B cell
             NHL that is refractory / recurrent.

          -  Participants must have been diagnosed with histologically confirmed B-ALL that is
             refractory / recurrent.

          -  Adequate performance status; adequate organ and marrow function as defined by
             (supportive care is allowed per institutional standards, i.e. filgrastim,
             transfusion):

          -  ANC ≥ 750/uL*

          -  Platelet count ≥ 50,000/uL*

          -  Absolute lymphocyte count ≥ 150/uL*

          -  Adequate renal, hepatic, pulmonary and cardiac function defined as:

               -  SaO2 ≥ 92% on room air

               -  Creatinine ≤ 2 mg/dL or Creatinine Clearance ≥ 60 mL/min (as estimated by
                  Cockcroft Gault)

               -  Total bilirubin ≤ 1.5 mg/dL (except in subjects with Gilbert's disease)
                  (Elevations related to leukemia or lymphoma involvement of the liver will not
                  disqualify a subject)

               -  Serum ALT/AST ≤3x ULN or ≤5X if there is hepatic involvement due to malignancy

               -  Cardiac ejection fraction (LVEF) ≥ 45%)

          -  Subjects with ALL or B-NHL with CNS1, or CNS1a, 2b, 2c are eligible only in the
             absence of neurologic symptoms suggestive of CNS disease involvement such as cranial
             nerve palsy.

          -  If patients previously had CNS disease and are disease free after treatment with no
             clinical concerns for recurrent disease they are eligible for enrollment.

          -  Subjects with history of allogeneic SCT must be at least 100 days from SCT, have no
             evidence of Graft versus Host Disease (GvHD), and no longer taking immunosuppressive
             agents for at least 30 days prior to enrollment. However, patients with grade 1 skin
             GVHD or low grade cGHVD <3 who are not requiring systemic therapy are eligible.

          -  Females of child bearing potential and males of child fathering potential must be
             willing to practice birth control during and for 4 months post therapy.

          -  Females of child bearing potential must have negative pregnancy test.

          -  Must meet wash out period since prior therapies.

               -  At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since
                  any prior systemic therapy at the time the subject is planned for leukapheresis,
                  except for systemic inhibitory/stimulatory immune checkpoint therapy, which
                  requires 5 half-lives

          -  Must have recovered from acute side effects from prior therapy to meet eligibility.

          -  If had prior CAR therapy, 30 days must have elapsed prior to apheresis; may not have
             evidence of persistence of CAR T cells in blood samples (circulating levels of
             genetically modified cells of ≥ 5% by flow cytometry)

          -  No active HIV or active HBV/HCV infection. Patients with history of HBV or HCV who are
             PCR negative after appropriate therapy are eligible. Patients may not have any other
             uncontrolled, symptomatic, intercurrent illness.

          -  No history of severe, immediate hypersensitivity reaction attributed to compounds of
             similar chemical or biologic composition to any agents used in study.

          -  No active CNS disorder, or history of MI, cardiac angioplasty or stenting, unstable
             angina or other clinically significant cardiac disease with 12 months of enrollment,
             or have cardiac atrial or ventricular lymphoma involvement.

          -  Not receiving anticoagulation therapy

          -  Not have primary immunodeficiency or history of autoimmune disease (e.g. Crohns,
             rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring
             systemic immunosuppression/systemic disease modifying agents within the last 2 years

        Exclusion Criteria:

          -  Participants must not have an active bacterial, viral, fungal or other infection.

          -  Participants must not have a history of HIV or current hepatitis B or hepatitis C
             virus

          -  Participants must not have a history of myocardial infarction, cardiac angioplasty or
             stenting, unstable angina, or other clinically significant cardiac disease within 12
             months of enrollment, or have cardiac atrial or cardiac ventricular lymphoma
             involvement.

          -  No history of severe, immediate hypersensitivity reaction attributed to compounds of
             similar chemical or biologic composition to any agents used in study.

          -  No active CNS disorder, or history of MI, cardiac angioplasty or stenting, unstable
             angina or other clinically significant cardiac disease with 12 months of enrollment,
             or have cardiac atrial or ventricular lymphoma involvement.

          -  Not receiving anticoagulation therapy

          -  Not have primary immunodeficiency or history of autoimmune disease (e.g. Crohns,
             rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring
             systemic immunosuppression/systemic disease modifying agents within the last 2 years

          -  History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g.
             cervix, bladder, and breast) unless disease free for at least 1 year. Patients who are
             on adjuvant therapy with no evidence of active disease are deemed eligible for the
             trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Successful production of CD19-CD34 CAR product that meet predefined release criteria (cell viability/cell number/transduction efficiency/negative sterility and viral testing) for enrolled patients
Time Frame:18 months
Safety Issue:
Description:24 participants evaluated for determination of the feasibility of producing CD19-CD34 CAR T cells meeting the established release criteria

Secondary Outcome Measures

Measure:Response to treatment
Time Frame:24 months
Safety Issue:
Description:24 participants evaluated for response to treatment by testing using PET/CT for lymphoma and using bone marrow aspirate for leukemia.
Measure:Progression free survival
Time Frame:24 months
Safety Issue:
Description:24 participants evaluated for progression by testing using PET/CT for lymphoma and using bone marrow aspirate for leukemia.
Measure:Overall survival
Time Frame:15 years
Safety Issue:
Description:24 participants evaluated for overall survival by clinical visit

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loyola University

Trial Keywords

  • Leukemia
  • Lymphoma
  • CAR T
  • Chimeric
  • CD19

Last Updated

December 30, 2019