Anti-CD19/4-1BB/CD3ζ CAR T-cell: autologous, unselected CD3+ lymphocytes collected from whole
blood or apheresis, transfected with a lentiviral vector containing a 2nd generation chimeric
antigen receptor (CAR) consisting of a scFv recognizing CD19 and dual co-stimulatory
intracellular signaling domains (4-1BB and CD3ζ). All patients will receive lymphodepleting,
conditioning chemotherapy in the form of cyclophosphamide (500 mg/m2/day) and fludarabine (30
mg/m^2/day) on Days -5, -4, and -3 prior to a CAR T-cell intravenous, single dose
administration on Day 0.
Phase 1b: Dose Finding/Escalation Dose Level 1: 0.5 x 10^6/kg Dose Level 2: 1.0 x 10^6/kg
Dose Level 3: 2.0 x 10^6/kg
Phase 2: Expansion Patients will receive lymphodepleting chemotherapy as indicated prior to
receiving the CAR T-cell intravenous, single dose administration on Day 0 at the RP2D as
identified during Phase 1b.
1. Have given written informed consent prior to any study-specific procedures; children
(defined as 17 years of age or less) require guardian consent.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; or Karnofsky > 50%.
3. Age of 2 to 70 years at time of screening.
4. A histologically or cytologically documented, CD19+ non-hodgkin's lymphoma or ALL.
5. At least 1 measurable lesion or FDG-avid disease by positron-emission
tomography/computed tomography (PET/CT) for lymphoma patients; quantifiable evidence
of ALL in either peripheral blood or bone marrow aspirate.
6. Tumor tissue (archival or recent acquisition) must be available for correlative
laboratory studies (such as immunohistochemistry, and others).
7. At least 2 prior systemic therapies and patient must not be eligible for potentially
curative standard-of-care therapy.
8. Adequate renal function (defined as Cockroft-Gault creatinine clearance > 50 mL/min)
and hepatic function (total bilirubin < 1.5x ULN; and AST/ALT < 3x ULN) unless
directly related to malignant disease being treated for on study as demonstrated
either by PET/CT imaging or by biopsy and histopathologic confirmation.
9. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate
of < 1% per year during the treatment period and for at least 90 days after the last
dose of study treatment. 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, established proper use of 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.
10. Male participants should agree to not donate sperm during study period (i.e. up to 2
years following CAR T-cell administration).
11. Male participants with reproductive potential must agree to use medical approved
contraceptives during the study and for 90 days following the last dose of study
12. Are reliable and willing to make themselves available for the duration of the study,
and are willing to follow study procedures.
1. Prior treatment with immunotherapy directly targeting T-cells (except anti-thymocyte
globulin [ATG]), CD19-directed antibody-based therapies (except blinatumomab), or
other gene therapy products.
2. Received any investigational drug/anti-cancer therapy within 30 days.
3. Concurrent participation in another therapeutic clinical trial.
4. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent)
within 7 days prior to blood collection for CAR T-cell product manufacture.
5. Donor lymphocyte infusion (DLI) within 4 weeks prior to leukapheresis.
6. Salvage or debulking chemotherapy within 1 week prior to blood collection for CAR
T-cell product manufacture.
7. Prior central nervous system (CNS) involvement.
8. Unresolved acute toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) v4.03 Grade >1 (or baseline, whichever is greater) from
prior anticancer therapy. Alopecia and other nonacute toxicities are acceptable.
9. An uncontrolled intercurrent illness including but not limited to ongoing or active
infection (including fever within 48 hours of screening), symptomatic congestive heart
failure (i.e., New York Heart Association [NYHA] Class 3 or 4), unstable angina
pectoris, clinically significant and uncontrolled cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.
10. Major surgical procedure within 30 days.
11. Known history of human immunodeficiency virus (HIV) or active infection requiring
therapy, or positive tests for hepatitis B surface antigen or hepatitis C ribonucleic
12. Any vaccination against infectious diseases (e.g., influenza, varicella) within 4
weeks (28 days) of initiation of study treatment.
13. A woman who is pregnant or breastfeeding.