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
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 Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Dose-limiting toxicity
Secondary Outcome
Complete remission
Condition
Recurrent B-Cell Non-Hodgkin Lymphoma
Intervention
Chimeric Antigen Receptor T-Cell Therapy
Study Arms / Comparison Groups
Treatment (CD20-specific CAR T cell, chemotherapy)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
50
Start Date
December 5, 2017
Completion Date
November 16, 2037
Primary Completion Date
November 16, 2024
Eligibility Criteria
Inclusion Criteria:
- 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:
- 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 with large cell lymphoma transformed from indolent lymphomas are eligible if
previously treated with anthracycline containing regimen for either the indolent or
large cell histology
- Patients with central nervous system (CNS) lymphoma need to meet one of the following
criteria:
- Primary CNS lymphoma:
- Progressive disease after 3 cycles or an inadequate response after at least
4 cycles of a high-dose methotrexate (MTX) containing regimen in the opinion
of the treating physician, OR
- Not eligible for MTX therapy due to commodities or tolerance issues per
treating physician OR
- Recurrent disease after an initial response to MTX-based treatment
- Secondary CNS lymphoma:
- An inadequate rtesponse to at least 2 cycles of a MTX containing regimen, OR
- Recurrent disease after an initial response to MTX-based treatment
- Patients must be 18 years of age or older, 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. For CLL and
lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (WM) patients, the screening
tumor biopsy can we waived for clinical reasons after discussion with the study
principal investigator (PI). For patients with CNS lymphoma, a screening tumor biopsy
is not required and evidence of CD20 expression can be documented from the original or
prior biopsies
- 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 >= 1.5
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
- For patients with CNS lymphoma, a lesion >= 1cm on brain or spine MRI is required
- Patients with waldenstrom macroglobulinemia (WM) without radiologic evidence of
disease are eligible if they have measurable disease, as defined by serum monoclonal
M-spike of >= 0.5 g/dL
- 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 >= 1.5 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. For patients with CNS lymphoma, a lesion >= 1 cm on the brain or
spine MRI is required. Patients with WM without radiologic evidence of disease are
eligible if they have measurable disease, as defined by serum IgM level >= 0.5g/dL
- 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
- Patients with systemic disease without radiologic evidence of CNS involvement and with
isolated CSF involvement detectable by flow cytometry are eligible for enrollment in
systemic disease cohorts if neurologically asymptomatic. CSF involvement is not an
exclusion for patients enrolled as a primary or secondary CNS lymphoma.
- 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). Maintenance anti-hormone
therapies for breast or prostate cancers are allowed and are not considered active
treatment
- 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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Mazyar Shadman, 206-606-4668, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT03277729
Organization ID
9738
Secondary IDs
NCI-2017-01595
Responsible Party
Sponsor
Study Sponsor
Fred Hutchinson Cancer Center
Collaborators
Mustang Bio
Study Sponsor
Mazyar Shadman, Principal Investigator, Fred Hutch/University of Washington Cancer Consortium
Verification Date
March 2023