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Assessment of the Safety and Feasibility of Administering T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-cell Lymphoma or Leukemia


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Follicular Lymphoma, Large Cell Lymphoma

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Trial Information

Assessment of the Safety and Feasibility of Administering T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-cell Lymphoma or Leukemia


Background:

We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen receptor
(CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling
domains of CD28 and CD3-zeta. The retroviral vector can be used to mediate genetic transfer
of this CAR to T cells with high efficiency (> 50%) without the need to perform any
selection.

In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T cells secreted
significant amounts of IFN-gamma and IL-2. Anti-CD19-CAR-transduced T cells could
specifically recognize and kill primary chronic lymphocytic leukemia cells.

Objectives:

Primary objectives (not applicable after Amendment E is approved):

Phase 1 and 2 portion:

-Determine the safety of the administration of anti-CD19-CAR engineered peripheral blood
lymphocytes and aldesleukin either with or without a nonmyeloablative conditioning regimen
in patients with B cell malignancies.

Phase 2 portion only:

-Determine if lymphocyte-depletion with fludarabine plus cyclophosphamide given prior to
infusion of anti-CD19-CAR-transduced T cells and aldesleukin can enhance persistence of the
anti-CD19-CAR-transduced T cells.

Secondary objectives:

Phase 1 and 2 portion:

-Determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes
and aldesleukin either with or without the non- myeloablative conditioning regimen cause
regression of B cell malignancies.

With approval of Amendment E (and F), this study will be a pilot safety and feasibility
study:

Primary objectives

-Determine the safety and feasibility of the administration of anti-CD19- CAR engineered
peripheral blood lymphocytes and aldesleukin with a nonmyeloablative conditioning regimen in
patients with B-cell malignancies.

Secondary objectives:

- Determine the in vivo survival of the anti-CD19-CAR-transduced T cells.

- Determine if the treatment regimen cause regression of B-cell malignancies.

With approval of amendment H, this study will no longer include aldesleukin:

Primary objectives

-Determine the safety and feasibility of the administration of anti-CD19- CAR engineered
peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with
B-cell malignancies.

Secondary objectives:

- Determine the in vivo survival of the anti-CD19-CAR-transduced T cells.

- Determine if the treatment regimen cause regression of B-cell malignancies.

Eligibility:

Patients of 18 years of age or older must:

- have a CD19-expressing B-cell malignancy of any type

- be a non-responder to, or recurred after one or more standard chemotherapy-containing
regimens for their malignancy

- currently require treatment due to progressive malignancy

- deemed to be incurable by standard therapy

- Patients may not have:

--a history of allogeneic stem cell transplantation

- CNS disease

Design:

- PBMC obtained by leukapheresis (approximately 5 times 109 cells) will be cultured in
the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell
proliferation.

- Transduction is initiated by exposure of approximately 108 to 5 times 108 cells to
retroviral vector supernatant containing the anti-CD19 CAR.

Prior to Amendment E

- This trial will have two phases. Phase I will be a dose escalation design to determine
the maximal tolerated dose of anti-CD19-CAR-transduced T cells. All patients in this
phase of the trial will receive fludarabine and cyclophosphamide chemotherapy for
lymphocytedepletion, and anti-CD19-CAR-transduced T cells followed by high dose
aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Initially three patients
will be treated at each dose level. Should a single patient experience a dose limiting
toxicity (DLT) at a particular dose level, three more patients would be treated at that
dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the
next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified,
three additional patients will be accrued at the next-lowest dose, for a total of 6, in
order to further characterize the safety of the maximum tolerated dose prior to
starting the phase II portion of the trial. If a dose limiting toxicity occurs in the
first cohort, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in
this cohort, the study will be terminated.

- In phase II of this trial, patients will be randomized to receive or to not receive a
nonmyeloablative but lymphocyte-depleting preparative regimen consisting of
cyclophosphamide and fludarabine prior to cell therapy. All patients will receive
anti-CD19-CAR-transduced T cells followed by high dose aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses). Patients will be stratified so that an equal number of
patients on each arm of phase II of the trial have peripheral blood total CD3 counts
less than 500 cells/microliter and an equal number of patients on each arm have a total
peripheral blood CD3 count greater than or equal to 500 cells/microliter. Randomization
will also be stratified so that an equal number of patients with circulating malignant
cells (leukemia) will be entered on each arm of the phase II part of the trial.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis, clinical laboratory evaluation, and other studies as
indicated by pretreatment disease site four to six weeks after treatment. Persistence
of anti-CD19-CARtransduced T-cells will be measured by flow cytometry. If the patient
has SD, PR or CR repeat complete evaluations will be performed every 1-3 months. After
the first year, patients continuing to respond will continue to be followed with this
evaluation every 3-4 months until off study criteria are met.

Starting with approval of Amendment E (discontinued with approval of amendment F)

- This trial will evaluate the safety and feasibility of the administration of
anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin with a
nonmyeloablative conditioning regimen in patients with B-cell malignancies. All
patients will receive fludarabine and cyclophosphamide chemotherapy for
lymphocyte-depletion, and between 1 times 10(9) and 1 times 10(10)
anti-CD19-CAR-transduced T cells followed by high dose aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses).

- Initially, 6 patients will be accrued to the protocol, if no more than 1 of the 6
patients has a DLT, then accrual will continue up to a total of 18 patients. If at any
time a cumulative total of 3 evaluable patients experience a DLT, then no further
patients will be enrolled.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis, clinical laboratory evaluation, and other studies as
indicated by pretreatment disease site four to six weeks after treatment. Persistence
of anti-CD19-CARtransduced T-cells will be measured by flow cytometry and/or
quantitative PCR. If the patient has SD, PR or CR repeat complete evaluations will be
performed every 1-3 months. After the first year, patients continuing to respond will
continue to be followed with this evaluation every 3-4 months until off study criteria
are met.

Starting with approval of Amendment F (discontinued with approval of amendment H):

- This trial will evaluate the safety and feasibility of the administration of
anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin with a
nonmyeloablative conditioning regimen in patients with B-cell malignancies. All
patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for
lymphocyte-depletion, and anti-CD19-CAR-transduced T cells followed by aldesleukin
(720,000 IU/kg or 72,000 IU/kg q8h for a maximum of 15 doses).

- With approval of amendment F, the trial is being refocused to evaluate the safety and
toxicity of the regimen studied at lower escalating dose levels since 3 DLTs were
observed at dose level 1 (between 1 times10(9) and 1 times10(10) cells). For cohort 2,
3 patients will be treated with NMA, 0.5 times 10(7) CAR positive cells/kg ( 20%), and
high dose aldesleukin (720,000 IU/kg). If one DLT is observed in a patient treated in
cohort 2, after analysis of the IFN-gamma cytokine data , 3 additional patients will be
treated at this dose level (0.5 x 10(7) CAR positive cells/kg ( 20%) after receiving
NMA followed by a reduced dose of aldesleukin (72,000 IU/kg q8h for a maximum of 15
doses) (cohort 3). If no DLTs are observed in the 3 patients in cohort 2 after analysis
of the IFN-gamma cytokine data, 3 additional patients will be treated with NMA, 1.0
times 107 CAR positive cells/kg ( 20%) and high dose aldesleukin (cohort 4). If one
DLT is observed in a patient treated in cohort 4, 3 additional patients will be treated
at this dose level (1.0 times 107 CAR positive cells/kg ( 20%) after receiving NMA
followed by a reduced dose of aldesleukin (72,000 IU/kg q8h for a maximum of 15 doses)
(cohort 5).

- The highest dose cohort evaluated with no DLTs in 3 patients (either 3, 4 or 5) will be
expanded to a total of 18 evaluable patients, subject to not exceeding 3 patients in
total with a DLT. Accrual will be halted to the study if none of the cohorts can be
expanded due to DLTs.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis, clinical laboratory evaluation, and other studies as
indicated by pretreatment disease site four to six weeks after treatment. Persistence
of anti-CD19-CARtransduced T-cells will be measured by flo cytometry and/or
quantitative PCR. If the patient has SD, PR or CR repeat complete evaluations will be
performed every 1-3 months. After the first year, patients continuing to respond will
continue to be followed with this evaluation every 3-4 months until off study criteria
are met.

Starting with approval of Amendment H:

- This trial will evaluate the safety and feasibility of the administration of
anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative
conditioning regimen in patients with B-cell malignancies. All patients will receive
fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, and
anti-CD19-CARtransduced T cells.

- With approval of amendment H, the trial is being refocused to evaluate the safety and

toxicity of the regimen studied at lower escalating dose levels of cells and in the absence
of

IL-2. Two new cohorts, designated cohort 6 and 7, will be added to this study. For cohort 6,

3 patients will be treated with NMA, and 0.5 x 107 CAR positive cells/kg ( 20%). If one

DLT is observed in a patient treated in cohort 6, after analysis of the IFN-gamma cytokine

data, accrual will be halted pending discussions with the FDA and IRB.

- One DLT was observed in cohort 6 in November 2011. The DLT was discussed with the FDA,
and the FDA indicated that we can treat an additional patient in cohort 6 (with
approval of amendment I). If this additional patient does not experience at DLT, cohort
6 will be expanded to a total of 6 patients. If any additional patients treated in
cohort 6 experiences a DLT, after analysis of the IFN-gamma cytokine data, accrual will
be halted pending discussions with the FDA and IRB.

- Another DLT was observed in cohort 6 in February 2012, and this cohort was closed. The
DLT was discussed with the FDA, and the FDA indicated that we can treat additional
patients in dose de-escalation cohorts using a 3 by 3 design.

- The highest dose cohort evaluated with no DLTs in 3 or more patients, or 1 DLT in 6
patients will be expanded to a total of 18 evaluable patients, subject to not exceeding
3 patients in total with a DLT. Accrual will be halted to the study if none of the
cohorts can be expanded due to DLTs.

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis, clinical laboratory evaluation, and other studies as
indicated by pretreatment disease site four to six weeks after treatment. Persistence
of anti-CD19-CARtransduced T-cells will be measured by flow cytometry and/or
quantitative PCR. If the patient has SD, PR or CR repeat complete evaluations will be
performed every 1-3 months. After the first year, patients continuing to respond will
continue to be followed with this evaluation every 3-4 months until off study criteria
are met.

Starting with approval of Amendment M:

- This trial will evaluate the safety and feasibility of the administration of
anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative
conditioning regimen in patients with B-cell malignancies. All patients will receive
fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, and
anti-CD19-CARtransduced T cells.

- Beginning with the approval of amendment M, Cohort 8 was closed. Patients will be
lymphodepleted with fludarabine and a reduced dose of cyclophosphamide - 30mg/kg/day
for 2 days and will receive 1 x10(6) CAR positive cells/kg ( 20%) as noted below.

- Cohort 9 will initially accrue 3 patients. If no DLTs are observed in these 3 patients,
three additional patients will be accrued. If DLTs are observed in less than or equal
to 1 patient out of 6 patients treated, this cohort will be expanded as described
below. If a DLT is observed in one of the first 3 patients, after analysis of the
cytokine data, 3 additional patients can be accrued to this 09-C-0082 6 cohort. If more
than 1 out of 6 patients in this cohort experiences a DLT, this cohort will be closed.
Subsequent dose reductions will be discussed with the FDA prior to initiation. If less
than or equal to 1 patient in 6 patients treated develops a DLT then the cohort will be
expanded to a total of 18 evaluable patients, subject to not exceeding 3 patients in
total with a DLT.

Inclusion Criteria


- INCLUSION CRITERIA:

1. Patient must have a CD19-expressing B cell malignancy of any type. Patients with
CLL, mantle cell lymphoma, and follicular lymphoma must have progressive or
stable disease after at least one standard chemotherapy regimen. Patients with
large cell lymphoma must have progressive or stable disease after at least two
prior chemotherapy regimens one of which must have contained doxorubicin and
rituximab. Patients with ALL must have relapsed or refractory disease after at
least one standard chemotherapy. CD19 expression must be detected on greater
than 50% of the malignant cells of each patient by immunohistochemistry or flow
cytometry.

2. CD19 expression must be detected on greater than 50% of the malignant cells by
immunohistochemistry or by flow cytometry in a CLIA approved test in the
Laboratory of Pathology, CCR, NCI, NIH. Definition of which cells are malignant
must be determined for each patient by the Laboratory of Pathology using
techniques to demonstrate monoclonality such as kappa/lambda restriction (other
techniques can be used to determine monoclonality at the discretion of the
Laboratory of Pathology). 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. Immunohistochemistry will be used for lymph node
biopsies; flow cytometry will be used for peripheral blood, fine needle
aspirates and bone marrow samples.

3. Patients must have indications for treatment for their B cell malignancy at the
time of enrollment on this trial.

4. Betweeen 18 and 70 years of age.

5. Willing to sign a durable power of attorney.

6. Able to understand and sign the Informed Consent Document.

7. Clinical performance status of ECOG 0 or 1.

8. Life expectancy of greater than three months.

9. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for four months after receiving the preparative
regimen.

10. Serology:

- 1. Seronegative for HIV antibody. (The experimental treatment being
evaluated in this protocol depends on an intact immune system. Patients who
are HIV seropositive can have decreased immune -competence and thus be less
responsive to the experimental treatment and more susceptible to its
toxicities.).

- 2. Seronegative for hepatitis B antigen and hepatitis C antibody unless
antigen negative.

11. Hematology:

- 1. Absolute neutrophil count greater than or equal to 1200/mm(3) without
the support of filgrastim.

- 2. Platelet count greater than or equal to 70,000/mm(3).

- 3. Hemoglobin greater than 8.0 g/dl.

- 4. Lymphocyte count less than or equal to 4,000/ mm(3)

12. Chemistry:

- 1. Serum ALT/AST less or equal to 5 times the upper limit of normal.

- 2. Serum creatinine less than or equal to 1.6 mg/dl

- 3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl

13. More than four weeks must have elapsed since any prior systemic therapy at the
time the patient receives the preparative regimen, and patients' toxicities must
have recovered to a grade 1 or less (except for toxicities such as alopecia or
vitiligo)

14. Normal cardiac ejection fraction and no evidence of pericardial effusion as
determined by an echocardiogram.

EXCLUSION CRITERIA:

1. Patients that require urgent therapy due to tumor mass effects such as bowel
obstruction or blood vessel compression.

2. Patients that have active hemolytic anemia.

3. Patients with detectable cerebrospinal fluid malignant cells or brain metastases or
with a history of cerebrospinal fluid malignant cells or brain metastases.

4. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

5. Active systemic infections, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.

6. Any form of primary immunodeficiency (such as Severe Combined

Immunodeficiency Disease).

7. Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).

8. Concurrent Systemic steroid therapy.

9. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

10. History of allogeneic stem cell transplantation

11. Patients with CNS metastases or symptomatic CNS involvement

(including cranial neuropathies or mass lesions).

12. CNS-3 disease or traumatic spinal tap with POSITIVE Steinherz/Bleyer algorithm with
cerebral spinal fluid involvement with

malignancy will make any patient not eligible for this protocol.

13. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety and feasibility of the administration of anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin with a nonmyeloablative conditioning regimen in patients with B-cell malignancies.

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

090082

NCT ID:

NCT00924326

Start Date:

February 2009

Completion Date:

April 2014

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma
  • Follicular Lymphoma
  • Large Cell Lymphoma
  • B Cell Malignancies
  • T Cell Persistence
  • Safety
  • Immunotherapy
  • Leukemia
  • Chronic Lymphocytic Leukemia
  • CLL
  • Lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphoma, Mantle-Cell

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892