Leukemia Clinical Trial
Official title:
Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies
Background:
- Although progress has been made in treating children with B-cell cancers such as leukemia
or lymphoma, many children do not respond to the standard treatments. One possible treatment
involves collecting white blood cells called T cells from the person with cancer and
modifying the cells to attack the B-cell cancer. The cells can then be given back to the
participant. This study will use T cells that have been modified to attack the cluster of
differentiation 19 (CD19) protein, which is found on the surface of some B-cell cancers.
Objectives:
- To see if anti-CD19 modified white blood cells are a safe and effective treatment for
children and young adults with advanced B-cell cancer.
Eligibility:
- Children and young adults between 1 and 30 years of age who have B-cell cancer (leukemia
or lymphoma) that has not responded to standard treatments.
- The leukemia or the lymphoma must have the CD19 protein.
- There must be adequate organ function.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine
samples will be collected. Imaging studies or bone marrow biopsies may be performed
depending on the type of cancer.
- Participants will undergo a process where white blood cells are collected, called
apheresis. These cells will be modified to contain the anti-CD19 gene.
- Participants will have 3 days of chemotherapy to prepare their immune system to accept
the modified cells.
- Participants will receive an infusion of their own modified white blood cells. They will
remain in the hospital until they have recovered from the treatment.
- Participants will have frequent follow-up visits to monitor the outcome of the
treatment.
- If the participant benefits from the treatment, then he/she may have the option for
another round of treatment.
Background:
Chimeric antigen receptors (CAR) that recognize the cluster of differentiation 19(CD19)
antigen have been constructed and are in clinical trials at several institutions. In this
trial, the Pediatric Oncology Branch (POB) will utilize a chimeric receptor containing the
signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3
(CD3)-zeta, currently under study in the Center for Cancer Research (CCR) in adults, for
children and young adults with CD19 expressing malignancies.
In co-cultures with CD19-expressing acute lymphoblastic leukemia cells,
anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly
clear CD19- expressing ALL cell lines.
Objectives:
1. 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. COMPLETED
March 2014.
2. Primary: To determine the safety of administering cells in two groups of children and
young adults with B-cell malignancies expressing CD19:
- Arm 1 - Patients without high-burden disease or patients for whom chemotherapy
toxicity is a concern will receive standard preparative regimen.
- Arm 2 - Patients with high-burden disease who receive standard chemotherapy to
reduce burden, (defined as patients with ALL who have M3 bone marrow blasts and/or
presence of peripheral blood blasts on routine complete blood count (CBC), or
patients with lymphoma).
3. Primary: To determine the feasibility of administering anti-CD19 CAR transduced T cells
within 21 days of the target date in children and young adults with B-cell malignancies
expressing CD19 enrolled on arm 2: Patients with high-burden disease who receive
standard chemotherapy to reduce burden.
1) Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral
blood lymphocytes can mediate antitumor effects in children with B cell high-burden disease
after standard chemotherapy, or in patients without high-burden disease who receive standard
preparative regimen. 2) To evaluate the ability of CRS treatment algorithm to reduce the
incidence of Grade 4 Cytokine Release Syndrome (CRS) to less than or equal to 10% of
patients. 3) To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T
cells in the blood, bone marrow and cerebrospinal fluid (CSF) of patients. 4) To describe the
toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in
children and young adults with central nervous system (CNS) disease.
Eligibility:
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 stem cell transplant who meet all eligibility criteria are eligible to
participate.
Design:
- PBMC will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from
fresh or frozen peripheral blood mononuclear cells (PBMCs). On Day -7, PBMC will be
enriched for cluster of differentiation 3 (CD3)+ cells and cultured in the presence of
anti-CD3/-cluster of differentiation 28 (CD28) beads followed by retroviral vector
supernatant containing the anti-cluster of differentiation 19 (CD19) CAR. Total culture
time is approximately 7-14 days.
- Patients will be divided into the 2 groups listed above.
Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m(2) on Days -4,
-3 and -2 and cyclophosphamide 900 mg/m(2) on day -2.
Arm 2: Patients with high-disease burden will be treated with intensive standard of care
chemotherapy to decrease disease burden during cell manufacturing.
- All patients: The CD19-CAR cells will be infused on Day 0, with up to a 72h delay
allowed for fresh cells or a 21 day delay if cells are cryopreserved, if needed for
resolution of clinical toxicities or to generate adequate cell numbers.
- The previously determined maximum tolerated dose (MTD) of 1 X 10(6) will be administered
intravenously.
- Patients will be monitored for toxicity, response and T cell persistence.
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