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A Pilot Study to Evaluate the Safety and Feasibility of Cellular Immunotherapy Using Genetically Modified Autologous CD20-Specific T Cells For Patients With Relapsed or Refractory Mantle Cell and Indolent B Cell Lymphomas


Phase 1
N/A
N/A
Open (Enrolling)
Both
B-cell Chronic Lymphocytic Leukemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma, Waldenström Macroglobulinemia

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Trial Information

A Pilot Study to Evaluate the Safety and Feasibility of Cellular Immunotherapy Using Genetically Modified Autologous CD20-Specific T Cells For Patients With Relapsed or Refractory Mantle Cell and Indolent B Cell Lymphomas


PRIMARY OBJECTIVES:

I. To assess the feasibility, safety and toxicity of cellular immunotherapy utilizing
ex-vivo expanded autologous T cells genetically modified to express a "second generation'
cluster of differentiation (CD)20-specific scFvFc:CD28:CD137:zeda chimeric immunoreceptor in
patients with recurrent or refractory CD20+ mantle cell or indolent lymphoma.

SECONDARY OBJECTIVES:

I. To determine the duration of in vivo persistence of adoptively transferred CD20-specific
T cells transfected with a CD20-specific scFvFc:CD28:CD137:zeda chimeric immunoreceptor.

II. To assess the trafficking of CD20-specific T cells to lymphoma masses. III. To evaluate
the development of host anti-CD20 scFvFc:CD28:CD137:zeda chimeric immunoreceptor and
anti-neomycin-resistance gene (NeoR) immune responses in study subjects.

OUTLINE:

CHEMOTHERAPY: Patients receive cyclophosphamide IV over 60 minutes.

IMMUNOTHERAPY: Beginning 2 days after completion of cyclophosphamide, patients receive
autologous CD20-specific T-cells IV over 30 minutes. Treatment repeats every 2-5 days for 3
courses.

MAINTENANCE THERAPY: Beginning 2 hours after the last T-cell infusion, patients receive
low-dose aldesleukin subcutaneously twice daily for 14 days.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Subjects who have achieved at least a partial remission lasting a minimum of 6 months may,
on a case-by-case basis, receive additional stored T cells following relapse.

After completion of study treatment, patients are followed up weekly for one month, monthly
for 1 year, and then annually for up to 2 years.


Inclusion Criteria:



- Male or female subjects with immuno histopathologically documented CD20+ mantle cell
lymphoma, follicular non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma/chronic
lymphocytic leukemia, marginal zone, or lymphoplasmacytic NHL of any age, gender, or
ethnic group who have relapsed or are refractory to conventional chemotherapy and who
are not eligible for Fred Hutchinson Cancer Research Center (FHCRC)/University of
Washington Medical Center (UWMC) transplant protocols (or who refuse participation in
transplant protocols)

- Willingness to sign an informed consent and undergo study tests

- Willingness to receive cytoreductive chemotherapy, if necessary to debulk tumors
prior to T cell administration, and to receive cyclophosphamide for lymphodepletion

- Serologic evidence of prior exposure to Epstein-Barr virus (EBV)

- Meets safety criteria to undergo leukapheresis

- Hemoglobin > 9.0 gm/dL

- White blood cell (WBC) > 2500 per microliter

- Alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x
Upper Limit of Normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x Upper Limit of Normal

- Creatinine =< 1.6 mg/dL

- Willingness to use acceptable (barrier or hormonal methods) birth control as
appropriate during the course of the study

Exclusion Criteria:

- Treatment with fludarabine or cladribine within the previous 2 years prior to
apheresis

- Known central nervous system involvement with NHL

- Pulmonary involvement with NHL; a diagnosis of pulmonary lymphoma will be based in
part on findings from chest computed tomography (CT) and, if clinically appropriate,
lung biopsy

- Exposure to chemotherapeutic agents (standard or experimental) or other
immunosuppressive therapies less than four weeks prior to apheresis; patients must
have recovered from acute side effects of such therapy

- Positive serology for human immunodeficiency virus (HIV)

- Active Hepatitis B or Hepatitis C infection

- History of hypersensitivity reactions to murine proteins or seropositivity for human
anti-mouse antibody (HAMA)

- Requirement for corticosteroid therapy during the study period unless used
specifically for amelioration of toxicity induced by transferred cells

- Treatment with anti-CD20 antibodies (rituximab, tositumomab, ibritumomab) within 4
months prior to start of T cell infusions

- Patients with lymph nodes in excess of 5 cm in diameter at time of T cell infusion

- Patients with > 5000 circulating CD20+ lymphocytes per mm^3 at time of T cell
infusion

- Previous allogeneic stem cell transplantation

- Life expectancy less than 90 days

- Pregnancy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Feasibility of transfecting and expanding the necessary numbers of T cells and the types of problems and toxicities which might be encountered, graded according the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0

Outcome Description:

A true grade 3 or higher toxicity rate in excess of 20% attributed to T cell infusions will be considered grounds for stopping the study and amending the protocol to lower the cell infusion doses. If there ever exists sufficient evidence to suggest that the true T cell-related toxicity rate (grade 3 or higher, with the exception of fever > 40 degrees Celsius lasting less than 24 hours) exceeds 20%, the study will be stopped.

Outcome Time Frame:

Up to 2 years after final T cell infusion

Safety Issue:

Yes

Principal Investigator

Brian Till

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

2154.00

NCT ID:

NCT00621452

Start Date:

August 2007

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Splenic Marginal Zone Lymphoma
  • Waldenström Macroglobulinemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Non-Hodgkin
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109