All clinical and laboratory data required for determining eligibility must be available in
the subject's medical/research record which will serve as the source document. Subjects may
be transfused with blood products to obtain a hemoglobin level > 7.0 g/dL and platelet
count > 20,000 per μl.
Note: During the period after cell procurement and during iC9-CAR19 T-cell production,
subjects are allowed to receive standard of care intervening therapy for ALL to manage
their disease if the treating physician feels it is in the subject's best interest Common
Inclusion Criteria for all subjects
- Written informed consent for procurement signed by subject or legal guardian of a
pediatric subject and HIPAA authorization
- Age 3 to 17 years of age for pediatric subjects (weight must be ≥10 kg), ≥ 18 to 70
years of age for adults at the time of consent.
- Karnofsky score > 60%, if ≥16 years old, or Lansky performance score of greater than
60% if <16 years old .
Demonstrate adequate renal and hepatic function as defined below; all screening labs to be
obtained within 72 hours prior:
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
- Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to procurement. Note: Females are considered of childbearing potential
unless they are premenarchal, surgically sterile (have undergone a hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or they 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 two forms of effective methods of contraception from
the time of informed consent until 3 months after treatment discontinuation. The two
contraception methods can be comprised of two 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 first dose of study therapy through 3 months after the last
dose of study therapy. As determined by the enrolling physician or protocol designee,
ability of the subject to understand and comply with study procedures.
Inclusion Criteria for Cell Procurement
- Relapsed or refractory 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 after 2 cycles of a
standard of care chemotherapy regimen, or
- For adult subjects: first bone marrow relapse with duration of first CR <1 year,
or CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of
relapse
- Subjects with isolated non-CNS extramedullary disease will be eligible as long as
the time-of-remission criteria above for bone marrow relapses or primary
refractory ALL are met and the biopsy for extramedullary disease confirms CD19
expression
- For pediatric subjects: first bone marrow or isolated non-CNS extramedullary
relapse refractory to 1 cycle of standard therapy for relapsed ALL
- While active CNS3 leukemia will be excluded, subjects with concurrent CNS3
disease and bone marrow relapse who have responded to CNS-directed therapy prior
to enrollment will be allowed to participate. Intrathecal chemotherapy will be
allowed to continue between lymphodepleting chemotherapy and cell infusion.
- Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible.
Intrathecal chemotherapy will be allowed to continue between lymphodepleting
chemotherapy and cell infusion
- Subjects who have previously achieved remission with no detectible measurable
residual disease (MRD) by multi-parameter flow cytometry, and who have re-
developed CD19+ MRD measured by multi-parameter flow cytometry will be eligible,
provided that the duration of first MRD-negative CR was <1 year, MRD- negative
CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of MRD
recurrence, or MRD reappearance occurs during second or subsequent CR.
- Subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry
after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after
one or more cycles of blinatumomab.
- Subjects with Ph+ ALL will be eligible if they have failed ≥ 2 ABL tyrosine kinase
inhibitors, relapsed after allogeneic stem cell transplant, or have CD19+ MRD as
described in section 4.1.4. Subjects with the T315I ABL kinase point mutation will be
eligible if they have failed ponatinib-containing therapy, regardless of the number of
prior ABL tyrosine kinase inhibitors.
- 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; all screening labs
to be obtained within 72 hours prior to procurement.
*For pediatric patients, adequate renal function is defined as below: Age Maximum
Serum Creatinine (mg/dL) Both (Male, Female) 3 to <6 years ≤0.8 6 to <10 years ≤1 10
to <13 years ≤1.2 13 to <16 years (Male) ≤1.5 / Female ≤1.4 16 to <18 years (Male)
≤1.7 / Female ≤1.4
- Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the
need for intrathecal prophylaxis prior to procurement is left to the discretion of the
investigator. 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 tyrosine kinase
inhibitors (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 for Cell Procurement
Subjects meeting any of the following criteria cannot be enrolled in this study:
- Subjects with relapsed fulminant CD19+ ALL that is 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 subjects with evidence of
CNS3 disease will be excluded from study entry. Subjects with concurrent CNS3 disease
and bone marrow relapse who have responded to CNS-directed therapy prior to
enrollment/lymphodepletion will be allowed to participate. Subjects with CNS2 disease
and concurrent bone marrow relapse will be eligible. Intrathecal chemotherapy will be
allowed to continue between cell procurement and lymphodepleting chemotherapy.
- Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the
milk is 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 five 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.
- Subjects must not have left ventricular ejection fraction of <40% (shortening fraction
<27% for pediatric subjects) as measured by echocardiogram or MUGA.
- Patients with the following systemic viral infections will be excluded: active HIV,
HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those
samples confirming lack of active infection will be used to generate transduced
cells). Note: To meet eligibility subjects are required to 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 Hepatitis B surface antigen, or negative for HCV antibody or
HCV viral load.
- Patients who are on treatment for other active uncontrolled infections (not referenced
above) 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 or its equivalent; those receiving <10 mg/day may be enrolled at discretion
of investigator. (Note: Corticosteroid use with doses at the discretion of the
treating physician are allowed after procurement up to the beginning of
lymphodepletion. 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 (within 2 weeks of procurement per section).
Inclusion Criteria for Lymphodepletion:
- Relapsed or refractory precursor B cell ALL, confirmed by presence of blasts in the
blood or bone marrow (≥5%) or in any extramedullary site. Subjects who have previously
achieved remission with no detectible measurable residual disease (MRD) by multi-
parameter flow cytometry, and who have re-developed CD19+ MRD measured by multi-
parameter flow cytometry are eligible, provided that the duration of first
MRD-negative CR was <1 year, MRD-negative CR1 duration ≥1 year and refractory to ≥1
cycle of therapy for treatment of MRD recurrence/relapse, or MRD-recurrence in second
or subsequent morphologic CR. Additionally, subjects who have persistent CD19+ MRD
measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and
have persistence of CD19+ MRD after one or more cycles of blinatumomab are eligible to
participate.
- Life expectancy ≥ 12 weeks.
- Subjects who have received prior therapy with murine antibodies must have
documentation of absence of human anti-mouse antibodies (HAMA) prior to
lymphodepletion on this study.
Demonstrate adequate renal and hepatic function as defined below; all screening labs to be
obtained within 72 hours prior to lymphodepletion.
- For pediatric patients, adequate renal function is defined as below:
Age Maximum Serum Creatinine (mg/dL) Both Male/Female 3 to <6 years ≤0.8 6 to <10 years ≤1
10 to <13 years ≤1.2 13 to <16 years (Male) ≤1.5/ (Female) ≤1.4 16 to <18 years (Male)
≤1.7/(Female) ≤1.4
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures.
- For subjects who receive chemotherapy between cell procurement and lymphodepletion,
washout periods as described in exclusion criteria sections 4.4.5 to 4.4.11 between
chemotherapy and the beginning of lymphodepletion will be required.
- Subjects must have autologous transduced activated T cells that meet the Certificate
of Analysis (CofA) acceptance criteria.
Exclusion Criteria for Lymphodepletion
Subjects meeting any of the following criteria cannot be enrolled in this study:
- Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the
milk is 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 five 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 (i.e., two weeks) prior to
lymphodepletion or has received any tumor vaccines within the previous five weeks
prior to lymphodepletion.
- Subject has received pegylated-asparaginase ≤3 weeks prior to lymphodepletion.
- Radiotherapy to a non-CNS site completed <1 week prior to lymphodepletion, or CNS
directed radiation completed <7 weeks prior to lymphodepletion.
- Subject is receiving following drugs <1 week prior to lymphodepletion: 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 lymphodepletion
(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 lymphodepleting
chemotherapy: tyrosine kinase inhibitors, 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 lymphodepleting chemotherapy .
- CNS prophylaxis with intrathecal methotrexate, cytarabine and/or hydrocortisome
treatment must be stopped prior to lymphodepleting chemotherapy.
- 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 Hepatitis B surface antigen, or negative for HCV antibody or
HCV viral load.
- Patients who are on treatment for other active uncontrolled infections (not referenced
above) 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. (Note:
Corticosteroid use with doses at the discretion of the treating physician are allowed
after procurement up to the beginning of lymphodepletion.).
Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.
Inclusion Criteria- iC9-CAR19 Cell Infusion
- Subjects must fulfill all of the following inclusion criteria to participate in this
study:
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures.
Exclusion Criteria- iC9-CAR19 Cell Infusion
- Subjects meeting any of the following criteria cannot be enrolled in this study:
- 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 lymphodepletion
may prompt exclusion from cell infusion at the discretion of the investigator.
- Received any donor lymphocyte infusions (DLI) ≤6 weeks prior to iC9-CAR19 T cell
product administration.
- Received any T cell lytic or toxic antibody (e.g. alemtuzumab) ≤8 weeks prior to iC9-
CAR19 T cell product administration (residual lytic levels may destroy the infused
iC9- CAR19 T cells and/or prevent their in vivo expansion).
Inclusion Criteria Prior to Lymphodepletion for the Second Infusion
- Life expectancy ≥ 12 weeks.
- Documentation of absence of human anti-mouse antibodies (HAMA). Demonstrate adequate
renal and hepatic function as defined below; all screening labs to be obtained within
72 hours prior to lymphodepletion.
Subject meets at least one of the following criteria:
- B-cell recovery (defined as absolute CD19+ cell count of >50/μL in the blood or bone
marrow CD19+ B cells ≥0.5% of marrow aspirate cells by flow cytometry) within 6 months
of initial infusion. Subjects who meet this criteria within 6 months of initial
infusion may be started on lymphodepletion at a date later than 6 months from initial
infusion.
- MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with
CD19+ expression at any time after initial infusion.
- At least 4 weeks have passed since the initial iC9-CAR19 T cell infusion.
- Subjects have resolved/recovered symptoms from CRS and/or ICANS that developed after
prior iC9-CAR19 T cell infusion.
- Subjects must have autologous transduced activated T cells that meet the Certificate
of Analysis (CofA) acceptance criteria. The subject must have sufficient available
cells or have sufficient stored peripheral blood to manufacture additional iC9-CAR19 T
cells.
Exclusion Criteria for Lymphodepletion for the Second Infusion
Subjects meeting any of the following criteria cannot receive a second infusion as part of
this study:
- Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the
milk is 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 five 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.
- Patients who are on treatment an 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. (Note:
Corticosteroid use with doses at the discretion of the treating physician are allowed
after procurement up to the beginning of lymphodepletion.).
Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.
Inclusion Criteria- Second iC9-CAR19 Cell Infusion
Subjects must fulfill all of the following inclusion criteria to receive a second iC9-
CAR19 cell infusion on this study:
Exclusion Criteria- Second iC9-CAR19 Cell Infusion
Subjects meeting any of the following criteria cannot receive a second iC9-CAR19 cell
infusion on this study:
- 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 lymphodepletion
may prompt exclusion from cell infusion at the discretion of the investigator
