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Phase I Study of Cellular Immunotherapy Using Central Memory-Enriched T Cells Lentivirally Transduced to Express a CD19-Specific, CD28-Costimulatory Chimeric Receptor and a Truncated EGFR Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma


Phase 1
18 Years
N/A
Not Enrolling
Both
Adult Grade III Lymphomatoid Granulomatosis, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Post-transplant Lymphoproliferative Disorder, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

Phase I Study of Cellular Immunotherapy Using Central Memory-Enriched T Cells Lentivirally Transduced to Express a CD19-Specific, CD28-Costimulatory Chimeric Receptor and a Truncated EGFR Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma


PRIMARY OBJECTIVES:

I. To assess the safety and describe the full toxicity profile of cellular immunotherapy
initializing ex vivo expanded autologous Tcm-enriched T cells that are genetically modified
using a self-activating (SIN) lentiviral vector to express a costimulatory cluster of
differentiation (CD)19-specific chimeric antigen receptors (CAR) as well as a truncated
human epidermal growth factor receptor (EGFR) (CD19R:CD28 zeta/EGFR tau +Tcm)
(CD19-CAR-specific/truncated EGFR lentiviral vector-transduced autologous T cells) in
conjunction with a standard myeloablative autologous hematopoietic stem cell transplant
(HSCT) for patients with high-risk intermediate grade B-lineage non-Hodgkin lymphoma.

II. To determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLTs).

SECONDARY OBJECTIVES:

I. To determine the tempo, magnitude, and duration of engraftment of the transferred T cell
product as it relates to the number of cells infused.

II. To study the impact of this therapeutic intervention on the development of normal CD19+
B-cell precursors in the bone marrow as a surrogate for the in vivo effector function of
transferred autologous CD19R:CD28 zeta/EGFR tau +Tcm.

OUTLINE: This is a dose-escalation study of CD19-CAR-specific/truncated EGFR lentiviral
vector-transduced autologous T cells.

Patients undergo mobilization for autologous stem cell collection with cytoreductive
chemotherapy and filgrastim and/or plerixafor per current standard operating policies. If
rituximab is not given as part of the salvage/priming chemotherapy regimen, patients receive
rituximab intravenously (IV) per standard practice within 4 weeks of the transplant.
Patients undergo myeloablative conditioning regimen per institutional standards beginning
day -7 followed by hematopoietic stem cell transplantation on day 0. Patients receive
CD19-CAR-specific/truncated EGFR lentiviral vector-transduced autologous T cells IV on day 2
or 3 (may be delayed up to day 45 if the patient is not yet eligible).

After completion of study treatment, patients are followed up weekly for 1 month, monthly
for 1 year, and then yearly for 15 years.


Inclusion Criteria:



- Research participants enrolled are patients with an indication to be considered for
HSCT, who are diagnosed with intermediate grade B-cell non-Hodgkin's lymphoma (NHL),
and that either have recurrence/progression following prior therapy, or verification
of high-risk disease in first remission as defined by "poor prognosis" histology

- Karnofsky performance status of >= 70% and a life expectancy >= 16 weeks at time of
enrollment

- The effects of autologous CD19R:CD28:zeta/EGFR tau+ Tcm on the developing fetus are
unknown; for this reason, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control or abstinence)
prior to study entry and for six months following duration of study participation;
should a woman become pregnant or suspect that she is pregnant while participating on
the trial, she should inform her treating physician immediately

- City of Hope (COH) pathology review confirms that research participant's diagnostic
material is consistent with the history of intermediate grade B-cell NHL

- History of recurrence/progression following prior therapy, or verification of
high-risk disease in first remission as defined by "poor prognosis" histology such as
mantle cell lymphoma

- Negative serum pregnancy test for women of childbearing potential

- Research participant has an indication to be considered for autologous stem cell
transplantation

- All patients must have the ability to understand and the willingness to sign a
written informed consent

- ELIGIBILITY TO UNDERGO AUTOLOGOUS MYELOABLATIVE TRANSPLANTATION WITH HEMATOPOETIC
PROGENITOR CELL (HPC)A RESCUE

- Research participant meets all standard clinical parameters for candidates of
autologous transplant as described in the current COH Hematopoietic Cell Transplant
Standard Operating Policies, Procedures and Protocols - Patient Evaluation &
Selection or Deferral for HCT

- Research participant is scheduled to receive a standard chemotherapy-based
conditioning regimen, such as cyclophosphamide, carmustine, etoposide (CBV) or
carmustine, etoposide, cytarabine, melphalan (BEAM)

- Research participant has a cryopreserved unselected HPCA product of at least 3 x
10^6/kg CD34+ cells

- Research participant does not have evidence of disease progression after salvage
therapy

- ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS

- Research participant has a released cryopreserved T cell product

- Research participant has undergone an autologous HPC(A) procedure

- Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation of 90%
or higher on room air

- Not requiring pressor support, not having symptomatic cardiac arrhythmias

- Lack of acute renal failure/requirement for dialysis, as evidenced by creatinine <
1.6

- Total bilirubin =< 5.0

- Research participant without clinically significant encephalopathy/new focal deficits

- No clinical evidence of uncontrolled active infections process

Exclusion Criteria:

- Research participants should not have any uncontrolled illness including ongoing or
active infection; research participants with known active hepatitis B or C infection;
research participants who are human immunodeficiency virus (HIV) seropositive based
on testing performed within 4 weeks of enrollment; research participants with any
signs of symptoms of active infection, positive blood cultures or radiological
evidence of infections

- Research participants may not be receiving any other investigational agents, or
concurrent biological, chemotherapy or radiation therapy; research participants who
are to receive radioimmunotherapy-based (Zevalin-based) conditioning regimens

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to rituximab and/or cetuximab

- Research participants with known brain metastases (central nervous system [CNS]
involvement or parenchymal or leptomeningeal involvement)

- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I/II study; evidence of
understanding includes passing the Protocol Comprehensive Screening given by the
Research Subject Advocate (RSA); a legal guardian may substitute for the research
participant

- Any standard contraindications to myeloablative HSCT per standard of care practices
at COH

- Dependence on corticosteroids

- Currently enrolled in another investigational therapy protocol

- HIV seropositive based on testing performed within 4 weeks of enrollment

- History of allogeneic HSCT or prior autologous HSCT

- Research participants with primary CNS lymphoma

- Active autoimmune disease requiring systemic immunosuppressive therapy

- Research participants with known active hepatitis B or C infection

- Research participants will be excluded, who in the opinion of the investigator, may
not be able to comply with the safety monitoring requirements of the study

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Adverse events attributed to Tcm adoptive transfer as reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Description:

Tables will be created to summarize all toxicities and side effects by dose, course, organ, and severity.

Outcome Time Frame:

Up to 15 years

Safety Issue:

Yes

Principal Investigator

Leslie Popplewell

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center

Authority:

United States: Federal Government

Study ID:

12224

NCT ID:

NCT01815749

Start Date:

June 2013

Completion Date:

Related Keywords:

  • Adult Grade III Lymphomatoid Granulomatosis
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Intraocular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Post-transplant Lymphoproliferative Disorder
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Hairy Cell Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell

Name

Location

City of Hope Medical CenterDuarte, California  91010