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

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.

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