| Eligibility |
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
1. Phase 1: Subject < 18 years of age and weighs = 6 kg at the time of signing the
informed consent form (ICF)/informed assent form (IAF).
Phase 2: Subject = 25 years of age and weighs = 6 kg at the time of signing the
ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and
voluntarily provide permission to the ICF/IAF prior to conducting any study-related
assessments/procedures.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
4. Investigator considers the subject is appropriate for adoptive T cell therapy.
5. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or
immunohistochemistry (bone marrow biopsy)
6. Subject has a Karnofsky score of = 50 (subjects = 16 years of age) or a Lansky score =
50 (subjects < 16 years of age).
7. Diagnosis of B-cell ALL or B-cell NHL as defined below:
Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM
(5% or greater lymphoblast by morphology) and either of the following:
- First or greater marrow relapse, or
- Any marrow relapse after allogeneic HSCT, or
- Primary refractory defined as not achieving a CR or a CRi after 2 or more
separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1
cycle of standard chemotherapy for relapsed leukemia), or
- Ineligible for allogeneic HSCT Note: Subjects will be included regardless of MRD
status.
Phase 2: Subjects with one of the following:
- Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or
greater lymphoblast by morphology) and either:
- First or greater marrow relapse, or
- Any marrow relapse after allogeneic HSCT, or
- Primary refractory defined as not achieving a CR or a CRi after 2 or more
separate induction regimens (or chemo-refractory as not achieving CR/CRi
after 1 cycle of standard chemotherapy for relapsed leukemia), or
- Ineligible for allogeneic HSCT.
- Cohort 2: MRD+ B-ALL, defined as:
- < 5% lymphoblasts by morphology with,
- MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM
cells. Subjects eligible for enrollment in Cohort 2 are those with MRD
positive morphologic CR2 after re-induction when these subjects had
previously experienced an early relapse (< 36 months) after first-line
chemotherapy. Subjects who are in MRD+ morphologic CR3 and later, regardless
of time to relapse in earlier lines, are also eligible. Subjects who are in
morphologic relapse at screening (r/r B-ALL) and become MRD+ after bridging
chemotherapy are also eligible for treatment in Cohort 2.
- Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as measurable disease after 1
or more lines of chemotherapy and/or having failed HSCT or being ineligible for
HSCT.
Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible however
subject selection must consider clinical risk factors for severe neurological AEs and
alternative treatment options. Subjects should only be enrolled if the Investigator
considers the potential benefit outweighs the risk for the subject.
8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant
to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if
TKI therapy is contraindicated.
9. Adequate organ function, defined as:
- Adequate BM function to receive LD chemotherapy as assessed by the Investigator.
- Subject with adequate renal function, which is defined as:
Serum creatinine based on age/gender as described below. Subjects that do not meet the
criteria but who have a creatinine clearance or radioisotope glomerular filtration
rate (GFR) > 70 mL/min/1.73 m2 are eligible.• Alanine aminotransferase (ALT) = 5 x
upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for
subjects with Gilbert's syndrome or leukemic/lymphomatous infiltration of the liver).
- Adequate pulmonary function, defined as = Grade 1 dyspnea according to Common
Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) = 92%
on room air.
- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) =
40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)
within 4 weeks prior to leukapheresis.
10. Adequate vascular access for leukapheresis procedure.
11. Participants must agree to use effective contraception
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject with a history of another primary malignancy that has not been in remission
for at least 2 years prior to enrollment.
5. Subjects who have received previous CD19-targeted therapy must have CD19-positive
disease confirmed since completing the prior CD19-targeted therapy.
6. Prior CAR T cell or other genetically-modified T cell therapy.
7. Subject with a previous history of or active hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV) infection.
8. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection
(including tuberculosis) despite appropriate antibiotics or other treatment at the
time of leukapheresis or JCAR017 infusion.
9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).
10. Subject with active autoimmune disease requiring immunosuppressive therapy.
11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6
months.
12. Subject with a concomitant genetic syndrome, with the exception of Down's syndrome.
13. Subject with active CNS disease and significant neurological deterioration. Subjects
with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not
have significant neurological deterioration and, in the opinion of the study
investigator, the CNS disease burden can be controlled until JCAR017 infusion.
14. Subject with a history or presence of clinically relevant CNS pathology such as
epilepsy, seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries,
dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or
psychosis.
15. Subject is pregnant or nursing.
16. Subject has used the following:
- Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg maximum 20 mg/day
prednisone or equivalent) within 7 days prior to leukapheresis or 72 hours prior
to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are
permitted.
- Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide = 300 mg/m2)
given after leukapheresis to maintain disease control must be stopped = 7 days
prior to LD chemotherapy.
- Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1
week prior to leukapheresis. Oral anticancer agents are allowed if at least 3
half-lives have elapsed prior to leukapheresis.
- Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide,
bendamustine) within 2 weeks prior to leukapheresis.
- Experimental agents within 4 weeks prior to leukapheresis unless no response or
PD is documented on the experimental therapy and at least 3 half-lives have
elapsed prior to leukapheresis.
- Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017
infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics,
mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as
antitumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).
- Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.
- Radiation within 6 weeks prior to leukapheresis. Subjects must have PD in
irradiated lesions or have additional non-irradiated lesions to be eligible.
Radiation to a single lesion, if additional non-irradiated, measurable lesions
are present, is allowed up to 2 weeks prior to leukapheresis.
- Allogeneic HSCT within 90 days prior to leukapheresis.
17. Tumor invasion of venous or arterial vessels (B-NHL subjects only).
18. Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to
leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to
leukapheresis, who still require ongoing therapeutic levels of anti-coagulation
therapy, are also excluded.
19. Existence of CD19-negative clone(s) of leukemia cells
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