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Cyclophosphamide

Fludarabine

Fludarabine phosphate

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Lymphodepleting regimen of Fludarabine and Cyclophosphamide.

Intensive standard of care chemotherapy, in lieu of the lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells.

Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.)

Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)

Nirali N Shah, M.D.

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.

Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma

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

Participants with B cell malignancies who received preparative chemotherapy followed by CD19 CAR T-cells with \< Grade 4 cytokine release syndrome.

Participants who had T-cells collected by apheresis and subsequently had the amount of CAR T-cells manufactured as prescribed by the dose level they were enrolled in.

Participants who were administered intensive chemotherapy prior to Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR): CD19 CAR infusion and received CAR cells within 21 days of the planned infusion date.

Measure persistence of adoptively-transferred anti-CD19-CAR transduced T cells (defined by percent of CD19 CAR T-cells) in the blood and where possible the bone marrow and Cerebrospinal Fluid (CSF) of patients by flow cytometry assay.

Complete Response (CR) was assessed by bone marrow evaluation was I defined as \<5% leukemic blasts.

Participants with Grade 4 Cytokine Release Syndrome (CRS). CRS is defined as a clinical syndrome that may occur after cell therapy due to the release of cytokines (substances secreted by immune cells) into the body's blood stream.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

Lymphodepleting regimen of Fludarabine and Cyclophosphamide. Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR): Cells extracted, followed by induction chemotherapy before CD19-CAR infusion.

Phase 1, Arm 1 - 1 x 10E6 Transduced T Cells/kg (+/- 20%)

Phase 1, Arm 2 - 3 x 10E6 Transduced T Cells/kg (+/- 20%)

Phase 2, Arm 1 - 1 x 10E6 Transduced T Cells/kg (+/- 20%)

Intensive lymphodepleting chemotherapy, in lieu of the standard lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells.

Anti-Cluster of Differentiation (CD)19- Chimeric antigen receptor (CAR): Cells extracted, followed by induction chemotherapy before CD19-CAR infusion.

Phase 2, Arm 2 - 1 x 10E6 Transduced T Cells/kg (+/- 20%)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Nirali N. Shah

Only 15/16 subjects were analyzed in Phase 2, Arm 1 because one subject did not received CAR cell infusion and therefore could not be evaluated for response.

Number of Participants Who Received Preparative Chemotherapy Followed by Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells With < Grade 4 Cytokine Release Syndrome

Per protocol, only patients treated in Phase 1 were analyzed for this outcome measure.

Number of Participants in Which the Prescribed Dose of Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells Were Successfully Manufactured

Per protocol, only participants on Phase 2, Arm 2 were analyzed for this outcome measure.

Number of Participants Who Were Administered Intensive Chemotherapy Prior to Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR Infusion

Peripheral blood

Bone marrow

Cerebrospinal fluid

Ph 1, Arm 1: BM analyzed in 13/16 subjects \& CSF in 14/16 subjects as results not available in additional subjects. Ph 2, Arm 1: 14/16 subjects analyzed as 1 not infused \& 1 developed PD. One additional subject didn't have BM/CSF results. Ph 2, Arm 2: 14/16 subjects analyzed as 2 developed PD. Two additional patients didn't have BM/CSF results.

Mean Percentage Cluster of Differentiation 19 (CD19) - Chimeric Antigen-Receptor (CAR) T-Cells in Blood, Bone Marrow (BM) and Cerebrospinal Fluid (CSF)

Number of Patients With a Complete Response (CR)

Number of Participants With Grade 4 Cytokine Release Syndrome (CRS)

Number of Participants With Serious and Non-Serious Adverse Events

Lymphodepleting regimen of Fludarabine and Cyclophosphamide.

Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR): Cells extracted, followed by induction chemotherapy before CD19-CAR infusion.

Follow-up through at least 28 days after CD19 CAR infusion.

Intensive lymphodepleting chemotherapy, in lieu of the standard lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells.

Anti-Cluster of Differentiation (CD)19- Chimeric antigen receptor (CAR): Cells extracted, followed by induction chemotherapy before CD19-CAR infusion.

Follow-up through at least 28 days after CD19 CAR infusion.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma	NCT01593696	ALL B Cell Lymphoma Leukemia Large Cell Lymp... Non-Hodgkin Lym...	Anti-Cluster of...	1 Year - 30 Years	National Institutes of Health Clinical Center (CC)
Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma	NCT01593696	ALL B Cell Lymphoma Leukemia Large Cell Lymp... Non-Hodgkin Lym...	Anti-Cluster of...	1 Year - 30 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cd 19 expressing b cells