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A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

NCT03277729

Description:

The purpose of this research is to find the best dose of genetically modified T-cells, to study the safety of this treatment, and to see how well it works in treating patients with B cell non-Hodgkin lymphoma that has come back or did not respond to previous treatment.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas
  • Official Title: A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 9738
  • SECONDARY ID: NCI-2017-01595
  • SECONDARY ID: 9738
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9217017
  • NCT ID: NCT03277729

Conditions

  • CD20 Positive
  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent Lymphoplasmacytic Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Follicular Lymphoma
  • Refractory Lymphoplasmacytic Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Transformed Non-Hodgkin Lymphoma
  • Recurrent Transformed B-cell Non-Hodgkin Lymphoma
  • Recurrent Transformed Chronic Lymphocytic Leukemia
  • Refractory Marginal Zone Lymphoma
  • Refractory Transformed B-cell Non-Hodgkin Lymphoma
  • Refractory Transformed Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
Chimeric Antigen Receptor T-Cell TherapyCAR T-cell therapyTreatment (CD20-specific CAR T cell, chemotherapy)
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 (CD20-specific CAR T cell, chemotherapy)
FludarabineFluradosaTreatment (CD20-specific CAR T cell, chemotherapy)

Purpose

The purpose of this research is to find the best dose of genetically modified T-cells, to study the safety of this treatment, and to see how well it works in treating patients with B cell non-Hodgkin lymphoma that has come back or did not respond to previous treatment.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) of adoptive cellular immunotherapy using ex
      vivo transduced and expanded autologous T cells expressing a third (3rd)-generation fully
      human CD20-specific chimeric antigen receptor (CAR) in patients with relapsed or refractory
      CD20+ B-cell non-Hodgkin lymphoma (B-NHL).

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and toxicity associated with CD20 CAR T cell infusions.

      II. To evaluate preliminary antitumor activity of adoptively transferred T cells in patients
      with measurable tumor burden prior to treatment as measured by overall response rate (ORR)
      and complete remission (CR) rate.

      III. To evaluate progression-free survival (PFS) and overall survival (OS) among patients
      treated with adoptively transferred CD20-specific T cells.

      OUTLINE: This is a phase I/II dose-escalation study of CD20-specific CAR T cell therapy.

      Patients undergo leukapheresis and may receive treatment after if needed for disease control.
      Patients then receive cyclophosphamide intravenously (IV). Patients may also receive
      fludarabine IV. After 36-96 hours, patients receive CD20-specific CAR T cell infusion.

      Patients will be actively participating in the study for approximately 15 months. The total
      time includes the time for the T cells to be made, the T cell infusion, and for approximately
      12 months after the T cell infusion is given. After completion of study treatment, patients
      are followed up for a minimum of 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CD20-specific CAR T cell, chemotherapy)ExperimentalPatients undergo leukapheresis and may receive treatment after if needed for disease control. Patients then receive cyclophosphamide IV. Patients may also receive fludarabine IV. After 36-96 hours, patients receive CD20-specific CAR T cell infusion.
  • Chimeric Antigen Receptor T-Cell Therapy
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have B-cell non-Hodgkin lymphoma, including mantle cell, follicular,
             lymphoplasmacytic, marginal zone, transformed indolent B cell lymphoma (including
             transformed chromic lymphoid leukemia [CLL]), or diffuse large B cell lymphoma that
             has relapsed after a response to at least one prior therapy regimen or is refractory
             to prior therapy; patients with de novo diffuse large B-cell lymphoma (DLBCL) must
             meet one of the following criteria:

               -  Biopsy-proven refractory disease after a frontline regimen containing both an
                  anthracycline and rituximab or other anti-CD20 antibody (i.e. "primary
                  refractory"), where any disease recurring within 6 months of completion of the
                  regimen is considered refractory

               -  Relapsed or refractory disease after at least one of the following:

                    -  At least 2 lines of therapy (including at least one with an anthracycline
                       and anti-CD20 antibody)

                    -  Autologous stem cell transplant

                    -  Allogeneic stem cell transplant

          -  Patients of any gender, race or ethnicity

          -  Patients must be capable of understanding and providing a written informed consent

          -  Negative serum pregnancy test within 2 weeks before enrollment for women of
             childbearing potential, defined as those who have not been surgically sterilized or
             who have not been free of menses for at least 1 year

          -  Fertile male and female patients must be willing to use an effective contraceptive
             method before, during, and for at least 4 months after the CAR T cell infusion

          -  Patients must have a Karnofsky performance status of >= 60%

          -  Confirmation of diagnosis by internal pathology review of initial or subsequent biopsy
             or other pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle
             Cancer Care Alliance (SCCA)/University of Washington (UW)/Harborview Medical Center
             (HMC)

          -  Evidence of CD20 expression by immunohistochemistry or flow cytometry on the tumor
             specimen obtained with the biopsy performed with screening; if the CD20 expression on
             the screening tumor biopsy is unclear or could not be assessed due to technical
             reasons, CD20 expression on a concomitant tumor specimen (such as marrow biopsy or
             circulating tumor cells) may be used to satisfy this requirement

          -  Serum creatinine =< 2.5

          -  Total bilirubin =< 3.0 mg/dL

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x the upper
             limit of normal

          -  Adequate pulmonary function, defined as =< grade 1 dyspnea and saturated oxygen (SaO2)
             >= 92% on room air; if pulmonary function test (PFT)s are performed based on the
             clinical judgment of the treating physician, patients with forced expiratory volume in
             1 second (FEV1) >= 50% of predicted and carbon monoxide diffusing capability (DLCO)
             (corrected) of >= 40% of predicted will be eligible

          -  Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >=
             50% as assessed by echocardiogram or multigated acquisition (MUGA) scan, or LVEF of
             45-49% and clearance by a cardiologist

          -  Measurable disease that can be accurately measured in at least one dimension as >= 2.0
             cm with computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI)
             techniques; extranodal disease that is measurable by fludeoxyglucose F-18
             (FDG)-positron emission tomography (PET) imaging only will also be allowed; note that
             if an excisional biopsy was performed that removed the sole site of measurable
             disease, the patient will not be eligible for leukapheresis and generation of CAR T
             cell product

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of uncontrolled active infection
             (bacterial, fungal, viral, mycobacterial) not responding to treatment with
             antibiotics, antiviral agents, or antifungal agents

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of active autoimmune disease
             requiring ongoing systemic immunosuppressive therapy

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Negative serum pregnancy test within 2
             weeks before lymphodepletion chemotherapy for women of childbearing potential, defined
             as those who have not been surgically sterilized or who have not been free of menses
             for at least 1 year

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: No treatment with any investigational
             agent on a different clinical trial between enrollment and lymphodepleting
             chemotherapy

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Serum creatinine =< 2.5

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Total bilirubin =< 3.0 mg/dL

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: AST and ALT =< 5 x the upper limit of
             normal

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Adequate pulmonary function, defined as
             =< grade 1 dyspnea and SaO2 >= 92% on room air; if PFTs are performed based on the
             clinical judgment of the treating physician, patients with FEV1 >= 50% of predicted
             and DLCO (corrected) of >= 40% of predicted will be eligible

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Adequate cardiac function, defined as
             left ventricular ejection fraction (LVEF) of >= 50% as assessed by echocardiogram or
             MUGA scan, or LVEF of 45-49% and clearance by a cardiologist; if subject receives
             cardiotoxic chemotherapy after enrollment, repeat echocardiogram or MUGA is required
             to reestablish eligible LVEF

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have a Karnofsky
             performance status of >= 60%

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Measurable disease that can be
             accurately measured in at least one dimension as >= 2.0 cm with CT, ultrasound, or MRI
             techniques; extranodal disease that is measurable by FDG-PET imaging only will also be
             allowed; note that if an excisional biopsy was performed that removed the sole site of
             measurable disease, the patient is not be eligible for lymphodepletion and CAR T cell
             infusion; measurable disease can be based on the imaging study done during the
             screening unless the patient received treatment in the interim, in which case imaging
             should be repeated

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must require no corticosteroid
             therapy or dose of less than 15 mg per day of prednisone or the equivalent; pulsed
             corticosteroid dose for disease control is acceptable until the day before the start
             of lymphodepletion

          -  ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have no active acute or
             chronic GVHD

        Exclusion Criteria:

          -  Active autoimmune disease requiring systemic immunosuppressive therapy

          -  Patients requiring corticosteroid therapy at a dose of 15 mg or more per day of
             prednisone or the equivalent; pulsed corticosteroid dose for disease control is
             acceptable

          -  Patients who are human immunodeficiency virus (HIV) seropositive

          -  Women who are pregnant or breastfeeding

          -  Significant cardiovascular diseases within the past 6 months including uncontrolled
             congestive heart failure (> New York Heart Association [NYHA] class II), myocardial
             infarction, unstable angina, or uncontrolled arrhythmia

          -  History of severe immediate hypersensitivity reaction to cyclophosphamide or
             fludarabine

          -  History or presence of clinically relevant non-lymphoma central nervous system
             pathology, including seizures that are uncontrolled on anticonvulsant therapy (>= 1
             seizure in the last year), paresis, aphasia, stroke, severe brain injuries, dementia,
             Parkinson disease, cerebellar disease, or psychosis

          -  Treatment with any investigational agent on a different clinical trial within 4 weeks
             prior to enrollment, unless the patient is documented to be unresponsive to the
             therapy and at least 3 half-lives have elapsed prior to enrollment

          -  Treatment with any anti-CD19 or anti-CD20 antibody or antibody-drug conjugate therapy
             within 4 weeks before enrollment

          -  Previous treatment with CD19-targeted CAR T cells that has resulted in ongoing B cell
             aplasia at the time of enrollment; patients that demonstrate recovery of normal B
             cells (>= 20 B cells/ul) by flow cytometry at any point 28 days or later after CD19
             CAR T cell infusion will be considered to have functional loss of CD19 CAR T cells and
             are potentially eligible

          -  Known active central nervous system metastases and/or lymphomatous meningitis;
             patients with isolated cerebrospinal fluid (CSF) involvement detectable by flow
             cytometry are eligible if clinically asymptomatic and if abnormal B cells are reported
             to be less than 3% by flow cytometry; subjects with previously treated central nervous
             system (CNS) disease may participate provided: 1) any CNS-directed treatment was
             completed at least 1 month prior to enrollment, 2) imaging studies and CSF evaluation
             show no evidence of disease progression, and 3) any neurologic symptoms have returned
             to baseline

          -  Presence of active acute or chronic graft versus host disease (GVHD)

          -  Uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding
             to treatment with intravenous antibiotics, antiviral or antifungal agents

          -  Patients with concurrent known additional malignancy that is progressing and/or
             requires active treatment; exceptions include squamous or basal cell carcinoma of the
             skin and low grade prostate carcinoma (Gleason grade =< 6)

          -  Patients with blood or platelet transfusion within 1 week prior to signing Consent A,
             or with platelets < 50,000/mm^3, neutrophils < 750/mm^3, or hemoglobin < 8.5 g/dL,
             unless the cytopenias are considered by the treating physician to be largely due to
             marrow involvement by lymphoma
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity
Time Frame:Up to 28 days
Safety Issue:
Description:Will be graded by Common Terminology Criteria for Adverse Events version 4.0.

Secondary Outcome Measures

Measure:Complete remission
Time Frame:Up to 15 years
Safety Issue:
Description:Will be assessed based on the Lugano criteria.
Measure:Progression-free survival (PFS)
Time Frame:Duration from study enrollment to progression or death due to any cause (whichever comes first), assessed up to 15 years
Safety Issue:
Description:A Cox proportional hazards model will be used to evaluate PFS.
Measure:Overall survival (OS)
Time Frame:Duration from study enrollment to death due to any cause, assessed up to 15 years
Safety Issue:
Description:A Cox proportional hazards model will be used to evaluate OS.
Measure:Incidence of adverse events
Time Frame:Up to 15 years
Safety Issue:
Description:Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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