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Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies

Phase 1
1 Year
30 Years
Open (Enrolling)
ALL, B Cell Lymphoma, Leukemia, Large Cell Lymphoma, Non-Hodgkin Lymphoma

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Trial Information

Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies


Chimeric antigen receptors (CAR) that recognize the CD19 antigen have been constructed and
are in clinical trials at several institutions. In this trial, the POB will utilize a
chimeric receptor containing the signaling domains of CD28 and CD3-zeta, currently under
study in the CCR in adults, for children and young adults with CD19 expressing malignancies.

In co-cultures with CD19-expressing acute lymphoblastic leukemia cells, anti-CD19
CARtransduced T cells show robust killing, and in xenograft models, can rapidly clear CD19-
expressing ALL cell lines.


Primary: To determine the safety and feasibility of administering escalating doses of anti-
CD19-CAR engineered peripheral blood lymphocytes in two strata (prior allogeneic stem cell
transplant -SCT- vs. no prior SCT) of children and young adults with B cell malignancies
following a cyclophosphamide/fludarabine preparative regimen.

Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral
blood lymphocytes can mediate antitumor effects in children with B cell malignancies. 2) To
measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood
and CSF of patients.


Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that
has recurred after or not responded to one or more standard chemotherapy-containing regimens
for their malignancy and is deemed incurable by standard therapy. Patients with a history of
allogeneic SCT who meet all eligibility criteria are eligible to participate.


On Day -11 PBMC will be obtained by leukapheresis, CD3+ cells enriched and cultured in the
presence of anti-CD3/-CD28 beads followed by retroviral vector supernatant containing the
anti-CD19 CAR. Total culture time is 13 days.

On Day -4, patients will begin induction chemotherapy comprising fludarabine 25 mg/m2 on
Days -4, -3 and -2 and cyclophosphamide 900 mg/m2 on day -2.

The CD19-CAR cells will be infused on Day 0, with up to a 48h delay allowed if needed for
resolution of clinical toxicities related to chemotherapy or to generate adequate cell

A phase I cell dose escalation scheme will be performed using 3 dose levels (1 x 106
transduced T cells/kg; 3 x 106 transduced T cells/kg; 1 x 107 transduced T cells/kg) in two
strata: patients who have undergone prior SCT and patients who have not previously undergone
SCT. Three patients will be enrolled at each dose level, with the cohort expanded to 6 if
dose limiting toxicity (DLT) occurs. If a cohort of patients previously treated with prior
SCT completes a dose level without DLT, patients in the other stratum (without previous SCT)
may dose escalate simultaneously. An expanded group of 12 patients at the maximum tolerated
dose (MTD) or the highest dose achieved if no MTD was determined, will be accrued to provide
additional information regarding the feasibility, safety and efficacy of this treatment.

Patients will be monitored for toxicity, response and T cell persistence.

Inclusion Criteria


- Patient must have a CD19-expressing B cell ALL or lymphoma and must have
relapsed or refractory disease after at least one standard chemotherapy and one
salvage regimen. In view of the PI and the primary oncologist, there must be no
available alternative curative therapies and subjects must be either ineligible
for allogeneic stem cell transplant (SCT), have refused SCT, or have disease
activity that prohibits SCT at this time.

- CD19 expression must be detected on greater than 15% of the malignant cells by
immunohistochemistry or greater than 30% by flow cytometry in a CLIA approved
test in the Laboratory of Pathology, CCR, NCI, NIH. The choice of whether to use
flow cytometry or immunohistochemistry will be determined by what is the most
easily available tissue sample in each patient. In general immunohistochemistry
will be used for lymph node biopsies, flow cytometry will be used for peripheral
blood and bone marrow samples.

- Patients must have measurable or evaluable disease at the time of enrollment,
which may include any evidence of disease including minimal residual disease
detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR)

- Greater than or equal to 1 year of age (and at least 15 kg) and less than or
equal to 30 years of age.

- Subjects with the following CNS status are eligible only in the absence of
neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

- CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on
cytospin preparation, regardless of the number of WBCs;

- CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for
blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm

- CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;

- CNS 2b: greater than or equal to10/uL RBCs; < 5/uL WBCs and cytospin
positive for blasts;

- CNS 2c: greater than or equal to 10/uL RBCs; greater than or equal to
5/uL WBCs and cytospin positive for blasts but negative by
Steinherz/Bleyer algorithm.

- Ability to give informed consent. For subjects < 18 years old their legal
guardian must give informed consent. Pediatric subjects will be included in age
appropriate discussion and verbal assent will be obtained for those greater than
or equal to 12 years of age, when appropriate.

- Clinical performance status: Patients > 10 years of age: Karnofsky greater than
or equal to 50%; Patients less than or equal to 10 years of age: Lansky scale
greater than or equal to 50%. Subjects who are unable to walk because of
paralysis, but who are upright in a wheelchair will be considered ambulatory for
the purpose of calculating the performance score.

- Patients of child-bearing or child-fathering potential must be willing to
practice birth control from the time of enrollment on this study and for four
months after receiving the preparative regimen.

- Females of child-bearing potential must have a negative pregnancy test because
of the potentially dangerous effects on the fetus.

- Cardiac function: Left ventricular ejection fraction greater than or equal to
greater than or equal to 40% by MUGA, fractional shortening greater than or
equal to 28% by ECHO or left ventricular ejection fraction greater than or equal
to 50% by ECHO.

- Patients with history of allogeneic stem cell transplantation are eligible if at
least 100 days post-transplant, if there is no evidence of active GVHD and no
longer taking immunosuppressive agents for at least 30 days prior to enrollment.


Subjects meeting any of the following criteria are not eligible for participation in the

- Recurrent or refractory ALL limited to isolated testicular or isolated central
nervous system (CNS) disease.

- Hepatic function: Inadequate liver function defined as total bilirubin > 2x upper
limit of normal (ULN) (except in the case of subjects with documented Gilberts
disease > 3x ULN) or transaminase (ALT and AST) > 5x ULN based on age- and
laboratory specific normal ranges;

- Renal function: Greater than age-adjusted normal serum creatinine (see Table below)
and a creatinine clearance < 60 mL/min/1.73 m(2).

- Age (Years) - greater than or equal to 5 - Maximum Serum Creatinine (mg/dL) -

- Age (Years) - 5 less than or equal to 10 - Maximum Serum Creatinine (mg/dL) -

- Age (Years) - greater than 10- Maximum Serum Creatinine (mg/dL) - 1.2

- Hematologic function:

- Absolute neutrophil count (ANC) < 750/microL, or platelet count <
50,000/microL, if these cytopenias are not judged by the investigator to be due
to underlying disease (i.e. potentially reversible with anti-neoplastic therapy)

- A subject will not be excluded because of pancytopenia greater than or equal to
Grade 3 if it is due to disease, based on the results of bone marrow studies.

- Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence

of greater than or equal to 5/(Mu)L WBCs in CSF and cytospin positive for blasts [in the
absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia);

- Hyperleukocytosis (greater than or equal to 50,000 blasts/?L) or rapidly progressive
disease that in the estimation of the investigator and sponsor would compromise
ability to complete study therapy;

- Pregnant or breast-feeding females;

- Recent prior therapy:

- Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas)
or radiation therapy less than or equal to3 weeks prior to apheresis;

- Exceptions:

- There is no time restriction in regard to prior intrathecal
chemotherapy provided there is complete recovery from any acute toxic
effects of such;

- Subjects receiving hydroxyurea may be enrolled provided there has been
no increase in dose for at least 2 weeks prior to starting apheresis

- Patients who relapse while receiving standard ALL maintenance
chemotherapy will not be required to have a waiting period before
entry onto this study provided they meet all other eligibility

- Subjects receiving steroid therapy at physiologic replacement doses
only are allowed provided there has been no increase in dose for at
least 2 weeks prior to starting apheresis;

- For radiation therapy: Radiation therapy must have been completed at
least 3 weeks prior to enrollment, with the exception that there is no
time restriction if the volume of bone marrow treated is less than 10%
and also the subject has measurable/evaluable disease outside the
radiation port.

- Other anti-neoplastic investigational agents currently or within 30 days
prior to apheresis (i.e. start of protocol therapy)

- Subjects must have recovered from the acute side effects of their prior
therapy, such that eligibility criteria are met. Cytopenias deemed to be
disease-related and not therapy-related are exempt from this exclusion.

- HIV/HBV/HCV Infection:

- Seropositive for HIV antibody. (Patients with HIV are at increased risk of
lethal infections when treated with marrow-suppressive therapy. Appropriate
studies will be undertaken in patients receiving combination antiretroviral
therapy in the future should study results indicate effectiveness.)

- Seropositive for hepatitis C or positive for Hepatitis B surface antigen

- Monoclonal antibody therapy administered within 5 half-lives of the agent prior
to apheresis;

- Uncontrolled, symptomatic, intercurrent illness including but not limited to
infection, congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, psychiatric illness, or social situations that would limit
compliance with study requirements or in the opinion of the PI would pose an
unacceptable risk to the subject;

.-.-. Second malignancy other than in situ carcinoma of the cervix, unless the
tumor was treated with curative intent at least two years previously and subject
is in remission;

- History of severe, immediate hypersensitivity reaction attributed to compounds
of similar chemical or biologic composition to any agents used in study or in
the manufacturing of the cells (i.e. gentamicin).

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the safety and feasibility of administering escalating doses of anti- CD19-CAR engineered peripheral blood lymphocytes in two strata prior allogeneic stem cell transplant ASCT vs. no prior ASCT in children plus young adults with B c...

Principal Investigator

Daniel W Lee, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

April 2012

Completion Date:

December 2015

Related Keywords:

  • ALL
  • B Cell Lymphoma
  • Leukemia
  • Large Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • CD 19 Expressing B Cells
  • B Cell Lymphoma
  • ALL
  • Anti-CD19 Chimeric Antigen Receptor
  • Adoptive Immunotherapy
  • Leukemia
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell



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