This study seeks to determine the safety of the treatment of relapsed or refractory B cell
lymphomas, relapsed/ refractory chronic lymphocytic leukemia and relapsed/refractory acute
lymphoblastic leukemia with chimeric antigen receptor T cells targeting CD19 and to find the
recommended phase II dose for this cellular therapy.
T cells are a type of white blood cell that helps the body fight infections. This treatment
uses T cells already present within the body that have been modified outside of the body by a
lentivirus and then returned to the participant by an infusion to target the cancer.
Lentivirus is a family of viruses that can be used by scientists to alter cells, which then
could be used to change the course of a disease. This type of treatment is sometimes referred
to as adoptive cell transfer (ACT). In this study the specific type of cells that will be
used is called human chimeric antigen receptor T cells (CAR-T cells). The CAR-T cells that
will be reinfused to the body are modified using a lentivirus that is no longer active. The
CAR-T cells will be returned to the body through an intravenous (IV) infusion. Another
purpose of this study is to learn about the side effects and toxicities related to this
treatment. Human CAR-T cell therapy is investigational (experimental) and works by removing T
cells from the blood and modifying them to be able to target the cancer.
Inclusion Criteria:
- Must have relapsed or refractory non-Hodgkin lymphoma (NHL) (Group A - NHL/CLL),
chronic lymphocytic leukemia (Group A - NHL/CLL) or acute lymphoblastic leukemia
(Group B - ALL) treated with at least two lines of therapy. Disease must have either
progressed after the last regimen or presented failure to achieve complete remission
with the last regimen.
- The participant's lymphoid malignancy must be cluster of differentiation antigen 19
(CD19) positive, either by immunohistochemistry or flow cytometry analysis on the last
biopsy available or peripheral blood for circulating disease.
- Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2
- Total bilirubin ≤ 1.5 times the institutional upper limit of normal
- AST (SGOT) ≤ 3 X institutional upper limit of normal
- ALT (SGPT) ≤ 3 X institutional upper limit of normal
- Serum Creatinine ≤ 2 X the institutional upper limit of normal unless bilirubin rise
is due to Gilbert's syndrome (maximum 2 times normal) or of non - hepatic origin.
- Must have adequate pulmonary function as defined as pulse oximetry ≥ 92% on room air.
- Must have adequate cardiac function as defined as left ventricular ejection fraction≥
40% in the most recent echocardiogram.
- Absolute Lymphocyte Count >100/microliter (uL)
- Participants (or legal guardians) must have the ability to understand and the
willingness to sign a written informed consent document.
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year during the treatment period and for at least 90 days after the human
anti-CD19 CAR-T cell infusion. A woman is considered to be of childbearing potential
if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous
months of amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus). Examples of
contraceptive methods with a failure rate of < 1% per year include bilateral tubal
ligation, male sterilization, hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices. The
reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
below: With female partners of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a failure
rate of < 1% per year during the treatment period and for at least 6 months after the
human anti-CD19 CAR-T cell infusion. Men must refrain from donating sperm during this
same period. With pregnant female partners, men must remain abstinent or use a condom
during the treatment period and for at least 6 months after the human antiCD19 CAR-T
cell infusion to avoid potential embryonal or fetal exposure. The reliability of
sexual abstinence should be evaluated in relation to the duration of the clinical
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
acceptable methods
Exclusion Criteria:
- Autologous transplant within 6 weeks of planned CAR-T cell infusion.
- Allogeneic stem cell transplant within 3 months of planned CAR-T cell infusion and
patients must be off immunosuppressive agents.
- Active graft versus host disease.
- Active central nervous system or meningeal involvement by lymphoma or leukemia.
Subjects with untreated brain metastases/central nervous system (CNS) disease will be
excluded from this clinical trial because of their poor prognosis and because they
often develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events.
- Participants with a history of CNS or meningeal involvement must be in a documented
remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced MRI imaging
for at least 90 days prior to registration.
- Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g.
cervix, bladder, breast).
- A minimum of 28 days must have elapsed between prior treatment with investigational
agent(s) and the day of lymphocyte collection.
- HIV seropositivity.
- Participants with uncontrolled intercurrent illness including, but not limited to
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social
situations that would limit compliance with study requirements.
- Pregnant or breastfeeding women are excluded from this study because CAR-T cell
therapy may be associated with the potential for teratogenic or abortifacient effects.
Women of childbearing potential must have a negative serum pregnancy test. Because
there is an unknown, but potential risk for adverse events in nursing infants
secondary to treatment of the mother with CAR-T cells, breastfeeding should be
discontinued. These potential risks may also apply to other agents used in this study.
- Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on
any bone marrow biopsy prior to initiation of therapy
- Serologic status reflecting active hepatitis B or C infection. Patients that are
positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
enrollment. (PCR positive patients will be excluded.)
- Participants with history of clinically relevant CNS pathology such as epilepsy,
seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe
brain injuries, dementia and Parkinson's disease.
- History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus
erythematosus) with requirement of immunosuppressive medication within 6 months.
