Inclusion Criteria - Cell Procurement
- Written informed consent for procurement signed by subject/legal guardian of pediatric
subject and HIPAA authorization
- Age 3-17 years of age for pediatric subjects (weight must be ≥10 kg), ≥18-70 years of
age for adults at time of consent
- Karnofsky score >60% (≥16 years old), Lansky performance score of >60% (<16 years old)
- Relapsed or refractory (R/R) precursor B cell ALL:
- 2nd or greater bone marrow relapse, or
- Any bone marrow relapse >100 days after allogeneic stem cell transplant, or
- Primary refractory ALL defined as no complete response (CR) after 2 cycles of
standard of care chemotherapy regimen, or
- For adult subjects: 1st bone marrow relapse with 1st CR <1 year, or CR1 ≥1 year
and refractory to ≥1 cycle of therapy for relapse
- Subjects with isolated non-CNS extramedullary disease will be eligible as long as
the time-of-remission criteria (above) are met and biopsy for extramedullary
disease confirms CD19 expression
- For pediatric subjects: 1st bone marrow or isolated non-CNS extramedullary
relapse refractory to 1 cycle of standard therapy for relapsed ALL
- While active CNS3 leukemia is excluded, subjects with concurrent CNS3 disease and
bone marrow relapse who responded to CNS-directed therapy prior to enrollment may
participate. Intrathecal chemotherapy will be allowed to continue between
lymphodepleting chemotherapy (LD) and cell infusion.
- Subject with CNS2 disease and concurrent bone marrow relapse are eligible.
Intrathecal chemotherapy will be allowed to continue between LD and cell infusion
- Subject previously achieving remission with no detectable measurable residual
disease (MRD) by multi-parameter flow cytometry, and who re-developed CD19+ MRD
measured by multi-parameter flow cytometry will be eligible, provided the 1st
MRD-negative CR was <1 year, MRD-negative CR1 duration ≥1 year and refractory to
≥1 cycle of therapy for MRD recurrence, or MRD reappearance occurs during
2nd/subsequent CR
- Subject with persistent CD19+ MRD measured by multi-parameter flow cytometry
after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after
≥1 cycles of blinatumomab
- Subject with Ph+ ALL will be eligible if failed ≥2 ABL tyrosine kinase inhibitors
(TKI) or relapsed after allogeneic stem cell transplant, or have CD19+ MRD. Subject
with the T315I ABL kinase point mutation eligible if have failed ponatinib-containing
therapy, regardless of number of prior ABL TKIs
- CD19 positivity of lymphoblasts confirmed by flow cytometry or IHC per institutional
standards
- Life expectancy ≥12 weeks
- Demonstrate adequate renal and hepatic function as defined below:
System Laboratory Value Renal*: Serum Creatinine (sCr) ≤ 1.5 × ULN Hepatic: Total bilirubin
(tBili) ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome; Aspartate aminotransferase
(AST) ≤ 3.0 × ULN; Alanine aminotransferase (ALT) ≤ 3.0 × ULN
*For pediatric patients, adequate renal function defined below: Age: Maximum sCr (mg/dL)
(Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13 years: ≤1.2,
≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4
- Females of childbearing potential (WOCBP) must have a negative serum pregnancy test
prior to procurement. Note: Females are considered of childbearing potential unless
are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are naturally postmenopausal for at least 12
consecutive months
- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 effective methods of contraception from informed
consent until 3 months after end of treatment. The 2 contraception methods can be
comprised of 2 barrier methods, or a barrier method plus a hormonal method. Female
participants will inform their male partners that they must use the methods of birth
control required by the protocol
- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the 1st dose of study therapy through 3 months after the last
dose of study therapy. As determined by enrolling physician/designee, ability of
subject to understand and comply with study procedures
- Subject currently receiving "maintenance" doses of chemotherapy eligible and need for
intrathecal prophylaxis prior to procurement is per investigator discretion.
Maintenance doses of systemic chemotherapy are defined as methotrexate ≤30 mg/m2/week,
mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. Maintenance therapy in
patients with Ph+ leukemia may also contain TKIs targeting BCR-ABL, at the discretion
of the investigator. Corticosteroid-containing maintenance therapy is permitted only
if corticosteroids are administered >14 days prior to procurement
Exclusion Criteria - Cell Procurement
- Subject with relapsed fulminant CD19+ ALL rapidly progressing with circulating
lymphoblasts that are rising in proportion to >50% of circulating white blood cells
- Lumbar puncture must be performed prior to procurement and subject with evidence of
CNS3 disease will be excluded from study entry. Subject with concurrent CNS3 disease
and bone marrow relapse who responded to CNS-directed therapy prior to enrollment/LD
allowed to participate. Subject with CNS2 disease and concurrent bone marrow relapse
are eligible. Intrathecal chemotherapy will be allowed to continue between cell
procurement and LD
- Pregnant/breastfeeding (Note: breast milk cannot be stored for future use if collected
while the mother is being treated on study)
- Has known active and/or progressive additional malignancy requiring treatment;
exceptions include basal cell or squamous cell skin cancer, in situ cervical or
bladder cancer, other cancer for which the subject has been disease-free for ≥5 years
- Subject must not have tumor in a location where enlargement could cause airway
obstruction
- Subject may not have an oxygen requirement as defined by pulse oximetry of <90% on
room air
- Subject must not have left ventricular ejection fraction of <40% (shortening fraction
<27% for pediatric subjects) as measured by echo or MUGA
- Patient with the following infections will be excluded: active HIV, HTLV, HBV, HCV.
Note: To meet eligibility subjects must not be positive for HIV antibody or HIV viral
load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for
Hep B surface antigen, or negative for HCV antibody or HCV viral load
- Patient on treatment for other active uncontrolled infections with resolution of
signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory
infections are not excluded. Other active uncontrolled infections will be excluded
- Prior to procurement current use of systemic corticosteroids at doses ≥10 mg/day
prednisone/equivalent; those receiving <10 mg/day may be enrolled at discretion of
investigator. Corticosteroid use is contraindicated following iC9-CAR19 infusion
unless medically necessary e.g., to treat CRS. Physiologic replacement with
hydrocortisone is allowed at doses 6-12 mg/m2/day, or equivalent
- Received anti-CD19 antibody-based therapy or cytotoxic chemotherapy not described as
maintenance therapy in inclusion 4.1.12 within 2 weeks of procurement
Inclusion Criteria - Lymphodepletion (LD)
- Written informed consent for the main study signed by subject/legal guardian of
pediatric subject.
- R/R precursor B cell ALL, confirmed by presence of blasts in the blood or bone marrow
(≥5%) or in any extramedullary site. Subject who previously achieved remission with no
detectable MRD by multi-parameter flow cytometry and re-developed CD19+ MRD measured
by multi-parameter flow cytometry are eligible, provided 1st MRD-negative CR was <1
year, MRD-negative CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for MRD
recurrence/relapse, or MRD-recurrence in 2nd or subsequent morphologic CR. Subjects
with persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of
initial chemotherapy and have persistence of CD19+ MRD after ≥1 cycles of blinatumomab
are eligible
- Karnofsky score >60%, (≥16 years old)/Lansky performance score >60% (if <16 years old)
- Life expectancy ≥12 weeks
- If prior therapy with murine antibodies must have documentation of absence of human
anti-mouse antibodies (HAMA) prior to LD on this study
- Demonstrate adequate renal and hepatic function as defined below System Laboratory
Value Renal*: sCr ≤1.5 × ULN Hepatic: tBili ≤1.5 × ULN, unless attributed to Gilbert's
Syndrome; AST ≤ 3.0 × ULN; ALT ≤3.0 × ULN
*For pediatric patients, adequate renal function defined below: Age: Maximum sCr
(mg/dL) (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13
years: ≤1.2, ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4
- WOCBP must have a negative serum pregnancy test
- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 3 months after treatment discontinuation. The 2
contraception methods can be comprised of 2 barrier methods, or a barrier method plus
a hormonal method. Female participants will inform their male partners that they must
use the methods of birth control required by the protocol
- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the 1st dose of study therapy through 3 months after the last
dose of study therapy
- As determined by the enrolling physician/designee, ability of the subject to
understand and comply with study procedures
- For subjects who receive chemotherapy between cell procurement and LD, washout periods
between chemotherapy and the beginning of LD will be required
- Subjects must have autologous transduced activated T cells that meet the Certificate
of Analysis (CofA) acceptance criteria
Exclusion Criteria - Lymphodepletion (LD)
- Pregnant/breastfeeding (Note: breast milk cannot be stored for future use if collected
while the mother is being treated on study)
- Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been
disease-free for at least 5 years
- Subjects must not have tumor in a location where enlargement could cause airway
obstruction
- Subjects may not have an oxygen requirement as defined by pulse oximetry of <90% on
room air
- Treatment with any investigational drug within 14 days prior to LD or has received any
tumor vaccines within the previous 5 weeks prior to LD
- Subject received pegylated-asparaginase ≤3 weeks prior to LD
- Radiotherapy to a non-CNS site completed <1 week prior to LD, or CNS directed
radiation completed <7 weeks prior to LD
- Subject receiving following drugs <1 week prior to LD: salvage chemotherapy (e.g.
clofarabine, cytosine arabinoside >100 mg/m2, anthracyclines, cyclophosphamide,
methotrexate ≥25 mg/m2)
- Any systemic drug used for GVHD must be stopped >3 weeks prior to LD (e.g. calcineurin
inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin,
thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF,
anti-IL6 or anti-IL6R, systemic steroids)
- The following drugs must be stopped prior to the beginning of LD: TKIs, hydroxyurea,
vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate <25 mg/m2, cytosine
arabinoside <100 mg/m2/day, and asparaginase (non-pegylated). These drugs should not
be administered concomitantly or following LD
- CNS prophylaxis with intrathecal methotrexate, cytarabine and/or hydrocortisone
treatment must be stopped prior to LD
- Patients with the following systemic viral infections will be excluded: active HIV,
HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV
antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for
HTLV1 and 2, negative for Hep B surface antigen, or negative for HCV antibody or HCV
viral load
- Patients who are on treatment for other active uncontrolled infections with resolution
of signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory
infections are not excluded. Other active uncontrolled infections will be excluded
- Use of systemic corticosteroids at doses ≥10 mg/day prednisone or its equivalent;
those receiving <10 mg/day may be enrolled at discretion of investigator. Physiologic
replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent
Inclusion Criteria- iC9-CAR19 Cell Infusion
- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from
informed consent until 3 months after treatment discontinuation. The 2 contraception
methods can be comprised of 2 barrier methods, or a barrier method plus a hormonal
method. Female participants will inform their male partners that they must use the
methods of birth control required by the protocol
- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with first dose of study therapy through 3 months after the last dose
of study therapy
- As determined by the enrolling physician/designee, ability of the subject to
understand and comply with study procedures
Exclusion Criteria- iC9-CAR19 Cell Infusion
- Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically
necessary (e.g., to treat CRS)
- Severe systemic uncontrolled disease or toxicities that develop after LD may prompt
exclusion from cell infusion at the discretion of the investigator
- Received any donor lymphocyte infusions (DLI) ≤6 weeks prior to cell infusion
- Received any T cell lytic or toxic antibody (e.g. alemtuzumab) ≤8 weeks prior to cell
infusion (residual lytic levels may destroy the infused iC9-CAR19 T cells and/or
prevent their in vivo expansion)