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
Study Details
Study Description
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
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 IV over 20-30 minutes.
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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 IV over 20-30 minutes. |
Biological: Chimeric Antigen Receptor T-Cell Therapy
Given CD20 CAR T cell IV
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Dose-limiting toxicity [Up to 28 days]
Will be graded by Common Terminology Criteria for Adverse Events version 4.0.
Secondary Outcome Measures
- Complete remission [Up to 15 years]
Will be assessed based on the Lugano criteria.
- Progression-free survival (PFS) [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) [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 [Up to 15 years]
Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients must have B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible lymphoma subtypes include (but not limited to): mantle cell, follicular, lymphoplasmacytic, marginal zone, transformed indolent B cell lymphoma (including transformed chronic 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 mantle cell lymphoma must have previously been treated with a Bruton tyrosine kinase (BTK) inhibitor and have either had disease progression, intolerance, or exposure to the drug for at least 3 months; patients with CLL/SLL are eligible if they had disease progression or intolerance to BTKis and/or a BCL-2 inhibitors; they are also required to have been treated with the other agent for at least 3 months (i.e. patients with progression/intolerance to BTKi need to be treated with a BCL-2 inhibitor for at least 3 months, and patients with progression/intolerance to BCL-2 inhibitor need at least 3 months of exposure to a BTKi); patients with de novo diffuse large B-cell lymphoma (DLBCL) must meet one of the following criteria:
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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
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Relapsed or refractory disease after at least one of the following:
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At least 2 lines of therapy (including at least one with an anthracycline and anti-CD20 antibody)
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Autologous stem cell transplant
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Allogeneic stem cell transplant
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Patients must be 18 years of age or older, of any gender, race or ethnicity
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Patients must be capable of understanding and providing a written informed consent
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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
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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
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Patients must have a Karnofsky performance status of >= 60%
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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)
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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
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Serum creatinine =< 2.5
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Total bilirubin =< 3.0 mg/dL
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x the upper limit of normal
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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
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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
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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
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with antibiotics, antiviral agents, or antifungal agents
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of active autoimmune disease requiring ongoing systemic immunosuppressive therapy
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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
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: No treatment with any investigational agent on a different clinical trial between enrollment and lymphodepleting chemotherapy
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Serum creatinine =< 2.5
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Total bilirubin =< 3.0 mg/dL
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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
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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
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have a Karnofsky performance status of >= 60%
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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
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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
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ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have no active acute or chronic GVHD
Exclusion Criteria:
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Active autoimmune disease requiring systemic immunosuppressive therapy
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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
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Patients who are human immunodeficiency virus (HIV) seropositive
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Women who are pregnant or breastfeeding
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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
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History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine
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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
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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
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Treatment with any anti-CD19 or anti-CD20 antibody or antibody-drug conjugate therapy within 4 weeks before enrollment
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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
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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
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Presence of active acute or chronic graft versus host disease (GVHD)
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Uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with intravenous antibiotics, antiviral or antifungal agents
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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). Maintenance anti-hormone therapies for breast or prostate cancers are allowed and are not considered active treatment
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Patients with blood or platelet transfusion within 1 week prior to signing Consent A, or with platelets < 50,000/mm3, neutrophils < 750/mm3, or hemoglobin < 8.5 g/dL, unless the cytopenias are considered by the treating physician to be largely due to marrow involvement by lymphoma
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fred Hutch/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- Mustang Bio
Investigators
- Principal Investigator: Mazyar Shadman, Fred Hutch/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 9738
- NCI-2017-01595
- 9738
- RG9217017