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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

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ClinicalTrials.gov Identifier: NCT03277729
Recruitment Status : Recruiting
First Posted : September 11, 2017
Last Update Posted : September 2, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE September 7, 2017
First Posted Date  ICMJE September 11, 2017
Last Update Posted Date September 2, 2019
Actual Study Start Date  ICMJE December 5, 2017
Estimated Primary Completion Date November 16, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
Dose-limiting toxicity [ Time Frame: Up to 28 days ]
Will be graded by Common Terminology Criteria for Adverse Events version 4.0.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03277729 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2019)
  • Complete remission [ Time Frame: Up to 15 years ]
    Will be assessed based on the Lugano criteria.
  • 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 ]
    A Cox proportional hazards model will be used to evaluate PFS.
  • Overall survival (OS) [ Time Frame: Duration from study enrollment to death due to any cause, assessed up to 15 years ]
    A Cox proportional hazards model will be used to evaluate OS.
  • Incidence of adverse events [ Time Frame: Up to 15 years ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
  • Complete remission [ Time Frame: Up to 15 years ]
    Will be assessed based on the Lugano criteria.
  • Incidence of adverse events [ Time Frame: Up to 15 years ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Overall survival [ Time Frame: Duration from study registration to death due to any cause, assessed up to 15 years ]
  • Progression-free survival [ Time Frame: Duration from study registration to progression or death due to any cause (whichever comes first), assessed up to 15 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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 (relapsed) or did not respond to previous treatment (refractory).
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Biological: Chimeric Antigen Receptor T-Cell Therapy
    Given CD20 CAR T cell IV
    Other Names:
    • CAR T-cell therapy
    • CAR T Infusion
    • CAR T Therapy
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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- 138719
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Procedure: Leukapheresis
    Undergo leukapheresis
    Other Names:
    • Leukocytopheresis
    • Therapeutic Leukopheresis
  • Drug: Fludarabine Phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • Beneflur
    • Fludara
    • Fludarabine-5''-Monophosphate
    • SH T 586
Study Arms  ICMJE Experimental: Treatment (CD20-specific CAR T cell, chemotherapy)
Patients 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.
Interventions:
  • Biological: Chimeric Antigen Receptor T-Cell Therapy
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Other: Laboratory Biomarker Analysis
  • Procedure: Leukapheresis
  • Drug: Fludarabine Phosphate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 7, 2017)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 16, 2037
Estimated Primary Completion Date November 16, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03277729
Other Study ID Numbers  ICMJE 9738
NCI-2017-01595 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9738 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG9217017 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Mazyar Shadman Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP