T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies



Status:Active, not recruiting
Conditions:Lymphoma, Lymphoma
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - 73
Updated:3/22/2019
Start Date:January 21, 2016
End Date:December 1, 2021

Use our guide to learn which trials are right for you!

T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies

Background:

The immune system fights infection and can affect cancer cells. T cells are white blood cells
that are a major part of the immune system. T cells can destroy tumors. Researchers want to
try to manipulate the immune system to better recognize and kill tumor cells.

Objective:

To test the safety of giving T cells expressing a novel fully-human anti-CD19 chimeric
antigen receptor (CAR) to people with advanced B-cell cancer.

Eligibility:

People ages 18 73 with a B-cell cancer that has not been controlled by other therapies.

Design:

Participants will be screened with:

Physical exam

Blood and urine tests

Heart tests

Bone marrow sample taken

Scans in machines that take pictures

Participants will have apheresis. Blood is removed through a needle in an arm. T cells are
removed. The rest of the blood is returned through a needle in the other arm.

The cells will be changed in a laboratory.

Participants will get 2 chemotherapy drugs over 3 days.

Two days later, participants will check into the hospital. They will get an intravenous (IV)
catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.

After this, participants will stay in the hospital for at least 9 days and stay nearby for 2
weeks. Then they will have blood tests and see a doctor.

Participants will have visits 6 visits for 1 year after the infusion. Some may have more
follow-up visits.

Participants may samples taken of spinal fluid, bone marrow, and tumors.

Background:

- Improved treatments for a variety of treatment-resistant B-cell malignancies including
Bcell lymphomas and chronic lymphocytic leukemia (CLL), are needed.

- A particular need is development of new treatments for chemotherapy-refractory B-cell
malignancies.

- T cells can be genetically modified to express chimeric antigen receptors (CARs) that
specifically target malignancy-associated antigens.

- Autologous T cells genetically modified to express CARs targeting the B-cell antigen
CD19 have caused complete remissions in a small number of patients with leukemia or
lymphoma. These results demonstrate that anti-CD19 CAR-expressing T cells have
antimalignancy activity in humans.

- The vast majority of B-cell malignancies express CD19.

- CD19 is not expressed by normal cells except for B cells.

- We have constructed a novel fully-human anti-CD19 CAR that can specifically recognize
CD19-expressing target cells in vitro and eradicate CD19-expressing tumors in mice.

- This fully-human CAR targeting CD19 has not been tested in humans before.

- Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
and neurological toxicities. Elimination of normal B cells is probable, and unknown
toxicities are also possible.

Objectives:

Primary

-Determine the safety and feasibility of administering T cells expressing a novel fully-human
anti-CD19 CAR to patients with advanced B-cell malignancies.

Secondary

- Evaluate the in vivo persistence and peak blood levels of anti-CD19 CAR T cells after
initial and repeated CAR T-cell infusions. CAR T-cell blood levels will be compared
retrospectively to results with an anti-CD19 CAR containing an antigen-recognition
moiety derived from a murine antibody.

- Assess for evidence of anti-malignancy activity by anti-CD19 CAR T cells

- Assess the impact of repeated CAR T-cell infusions on residual malignancy after an
initial CAR T-cell infusion.

- Assess the immunogenicity of the CAR used in this protocol.

Eligibility:

- Patients must have any B-cell lymphoma, or CLL/SLL. Lower grade lymphomas transformed to
DLBCL are potentially eligible as is primary mediastinal B-cell lymphoma and all other
subtypes of DLBCL.

- Patients must have malignancy that is measurable on a CT scan or by flow cytometry of
bone marrow or blood.

- Patients must have a creatinine of 1.4 mg/dL or less and a normal cardiac ejection
fraction.

- An ECOG performance status of 0-1 is required.

- No active infections are allowed including any history of hepatitis B or hepatitis C.

- Absolute neutrophil count greater than or equal to1000/microliter, platelet count
greater than or equal to 45,000/microliter, hemoglobin greater than or equal to 8g/dL

- Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal
unless liver involvement by malignancy is demonstrated.

- At least 14 days must elapse between the time of any prior systemic treatment (including
corticosteroids) and initiation of protocol enrollment.

- The patient s malignancy will need to be assessed for CD19 expression by flow cytometry
or immunohistochemistry performed at the NIH. If unstained, paraffinembedded bone marrow
or lymphoma sections are available from prior biopsies, these can be used to determine
CD19 expression by immunohistochemistry; otherwise, patients will need to come to the
NIH for a biopsy to determine CD19 expression. The sample for CD19 expression can come
from a biopsy obtained at any time before enrollment.

- Patients who have never had an allogeneic hematopoietic stem cell transplant are
potentially eligible.

Design:

- This is a phase I dose-escalation trial

- Patients will undergo leukapheresis

- T-cells obtained by leukapheresis will be genetically modified to express an anti-CD19
CAR

- Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
intent of enhancing the activity of the infused anti-CD19-CAR-expressing T cells.

- The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m(2) daily for 3 days
and fludarabine 30 mg/m(2) daily for 3 days. Fludarabine will be given on the same days
as the cyclophosphamide.

- Two days after the chemotherapy ends, patients will receive an infusion of
anti-CD19-CAR-expressing T cells.

- The initial dose level of this dose-escalation trial will be 0.66x10(6) CAR+ T cells/kg
of recipient bodyweight.

- The cell dose administered will be escalated until a maximum tolerated dose is
determined.

- Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to
monitor for toxicity.

- Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 6, 9, and 12 months after the
CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a
doctor near the patient s home for 4 more years and then yearly telephone contact for 10
additional years will be required.

- Repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell
infusion are planned for eligible patients with any best responses except continuing
complete remission or progressive malignancy.

- Re-enrollment will be allowed for a small number of subjects.

- INCLUSION CRITERIA:

- Malignancy criteria:

- Patients with the following malignancies are potentially eligible: any B-cell
lymphoma, and chronic lymphocytic leukemia (CLL). Patients with indolent
malignancies that have transformed to diffuse large B-cell lymphoma are eligible.

- Clear CD19 expression must be uniformly detected on 75% or more of malignant
cells from either bone marrow or a leukemia or lymphoma mass by flow cytometry or
immunohistochemistry. These assays must be performed at the National Institutes
of Health. It is preferable but not required that the specimen used for CD19
determination comes from a sample that was obtained after the patient s most
recent treatment. If paraffin embedded unstained samples of bone marrow involved
with malignancy or a lymphoma mass are available, these can be shipped to the NIH
for CD19 staining; otherwise, new biopsies will need to be performed for
determination of CD19 expression.

- DLBCL patients must have received at least two prior chemotherapy-containing
regimens at least one of which must have contained doxorubicin and a monoclonal
antibody. Follicular lymphoma patients must have received at least 2 prior
regimens including at least 1 regimen with chemotherapy. All other lymphoma and
leukemia patients must have had at least 1 prior chemotherapy-containing regimen.
All patients with CLL or small lymphocytic lymphoma must have had prior treatment
with ibrutinib or another signal transduction inhibitor.

- Patients must have measurable malignancy as defined by at least one of the
criteria below.

- Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest
diameter) by CT scan is required for all diagnoses except CLL. All masses
must be less than 10 cm in the largest diameter.

- For a lymphoma mass to count as measurable malignancy, it must have
abnormally increased metabolic activity when assessed by positron emission
tomography (PET) scan.

- For CLL and lymphoma with only bone marrow involvement no mass is necessary,
but if a mass is not present, bone marrow malignancy must be detectable by
flow cytometry in lymphoma and CLL.

- Other inclusion criteria:

- Greater than or equal to 18 years of age and less than or equal to age 73.

- Able to understand and sign the Informed Consent Document.

- Clinical performance status of ECOG 0-1

- Room air oxygen saturation of 92% or greater

- Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for four months after receiving the preparative
regimen.

- Women of child bearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the preparative chemotherapy on the fetus.
Women of child-bearing potential are defined as all women except women who are
post-menopausal

or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55
who have not had a menstrual period in at least 1 year.

- Seronegative for HIV antibody. (The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who are HIV seropositive can
have decreased immune -competence and thus are less responsive to the experimental
treatment and more susceptible to its toxicities.)

- Patients with a known history of hepatitis B or hepatitis C are not eligible due to
the risk of re-activation of hepatitis after prolonged B-cell depletion due to
anti-CD19 CAR T cells.

- Seronegative for hepatitis B antigen, positive hepatitis B tests can be further
evaluated by confirmatory tests, and if confirmatory tests are negative, the patient
can be enrolled. Patients with a known history of hepatitis B are not eligible.

- Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody
test is positive, then patients must be tested for the presence of RNA by RT-PCR and
be HCV RNA negative. Patients with a known history of hepatitis C are not eligible.

- Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of
filgrastim or other growth factors.

- Platelet count greater than or equal to 45,000/mm(3) without transfusion support

- Hemoglobin greater than 8.0 g/dl.

- Less than 5% malignant cells in the peripheral blood leukocytes

- Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal
unless liver involvement by malignancy is demonstrated.

- Serum creatinine less than or equal to 1.4 mg/dL.

- Total bilirubin less than or equal to 2.0 mg/dl.

- At least 14 days must have elapsed since any prior systemic therapy prior to apheresis
and prior to the initiation of chemotherapy (including systemic corticosteroids at any
dose). Because this protocol requires collection of autologous blood cells by
leukapheresis

in order to prepare CAR T cells, systemic anti-malignancy therapy including systemic
corticosteroid therapy of any dose are not allowed within 14 days prior to the required
leukapheresis. NOTE: Because of the long half-life and potential to affect CAR T cells, 60
days must elapse from the time of administration of anti-PD-1 or anti-PD-L1 antibodies or
other agents that in the opinion of the PI can stimulate immune activity and infusion of
CAR T cells.

- Normal cardiac ejection fraction (greater than or equal to 55% by echocardiography)
and no evidence of hemodynamically significant pericardial effusion as determined by
an echocardiogram within 4 weeks of the start of the treatment protocol.

- Patients must not take corticosteroids including prednisone, dexamethasone or any
other corticosteroid for 14 days before apheresis and CAR T-cell infusion. Patients
must also not take corticosteroids at doses higher than 5 mg/day of prednisone or
equivalent at any

time after the CAR T cell infusion.

--Patients who have been treated on other protocols of genetically-modified T cells at the
NIH only are potentially eligible under these conditions:

---At least 6 months have elapsed since the last genetically-modified T-cell therapy that
the patient received and there is no evidence of replication-competent retroviruses
(evidence must be provided from prior NIH gene-therapy protocol Principal Investigator) and
persisting genetically-modified T cells are not detectable in the patient s blood (evidence
must be provided by prior NIH gene-therapy protocol Principal Investigator).

EXCLUSION CRITERIA:

- Patients that require urgent therapy due to tumor mass effects or spinal cord
compression.

- Patients that have active hemolytic anemia.

- Patients with second malignancies in addition to their B-cell malignancy are not
eligible if the second malignancy has required treatment (including maintenance
therapy) within the past 4 years or is not in complete remission. There are two
exceptions to this

criterion: successfully treated non-metastatic basal cell or squamous cell skin carcinoma.

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

- Active uncontrolled systemic infections (defined as infections causing fevers and
infections requiring intravenous antibiotics when intravenous antibiotics have been
administered for less than 72 hours), active coagulation disorders or other major
uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal,
gastrointestinal, genitourinary or immune system, history of myocardial infarction,
history of ventricular tachycardia or ventricular fibrillation, active cardiac
arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation
not requiring current treatment is allowed (anticoagulants count as current treatment)
), active obstructive or restrictive pulmonary disease, active autoimmune diseases
such as rheumatoid arthritis.

- Patients will not be seen for screening appointments or enrolled on the protocol if
they have been hospitalized within the 7 days prior to the screening appointment or
the date of protocol enrollment.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days
prior to the required leukapheresis, or the initiation of the conditioning
chemotherapy regimen. Corticosteroid creams, ointments, and eye drops are allowed.

- History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

- Patients with current CNS involvement by malignancy (either by imaging or
cerebrospinal fluid involvement or biopsy-proven).
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Phone: 888-624-1937
?
mi
from
Bethesda, MD
Click here to add this to my saved trials