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Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00621452
First received: February 21, 2008
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

This phase I trial is studying the side effects of giving genetically engineered lymphocytes together with cyclophosphamide and aldesleukin in treating patients with relapsed or refractory mantle cell lymphoma or indolent B-cell non-Hodgkin lymphoma. Placing a gene that has been created in the laboratory into white blood cells may make the body build an immune response to kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Aldesleukin may stimulate the white blood cells to kill lymphoma cells. Giving genetically engineered lymphocytes together with cyclophosphamide and aldesleukin may be an effective treatment for mantle cell lymphoma and B-cell non-Hodgkin lymphoma


Condition Intervention Phase
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
Biological: therapeutic autologous lymphocytes
Drug: cyclophosphamide
Biological: aldesleukin
Genetic: polymerase chain reaction
Genetic: gene rearrangement analysis
Procedure: lymph node biopsy
Biological: genetically engineered lymphocyte therapy
Procedure: bone marrow aspiration
Other: flow cytometry
Other: laboratory biomarker analysis
Other: enzyme-linked immunosorbent assay
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • 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 [ Time Frame: Up to 2 years after final T cell infusion ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Comparison of the percentages of CD20-specific T cells and malignant B cells present in the blood before and after each T cell infusion [ Time Frame: Up to 4 weeks after the third infusion ] [ Designated as safety issue: No ]
    Numbers and percentages of CD20-specific T cells and of malignant B cells will also be quantified in lymph node (LN) and bone marrow (BM).

  • Immune response as assessed by ELISA and percent chromium release in cytotoxicity assays [ Time Frame: Up to 12 months following treatment ] [ Designated as safety issue: No ]
    Means, medians and standard deviation (S.D.) of the Ab titers observed will be computed.

  • Absolute numbers of T cells expressing the chimeric T Cell receptor (cTCR) per cubic uL of blood [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: August 2007
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (autologous CD20 specific T-cells)

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.

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.

Biological: therapeutic autologous lymphocytes
Given IV
Other Names:
  • AL
  • Autologous Lymphocytes
  • autologous T cells
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Biological: aldesleukin
Given subcutaneously
Other Names:
  • IL-2
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: gene rearrangement analysis
Correlative studies
Procedure: lymph node biopsy
Optional correlative studies
Other Name: Biopsy of Lymph Node
Biological: genetically engineered lymphocyte therapy
Receive genetically modified T cells
Procedure: bone marrow aspiration
Optional correlative studies
Other: flow cytometry
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: enzyme-linked immunosorbent assay
Correlative studies
Other Name: ELISA

Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00621452

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Brian Till Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided by Fred Hutchinson Cancer Research Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00621452     History of Changes
Other Study ID Numbers: 2154.00, NCI-2010-00416
Study First Received: February 21, 2008
Last Updated: August 4, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Waldenstrom Macroglobulinemia
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Plasma Cell
Paraproteinemias
Vascular Diseases
Aldesleukin
Cyclophosphamide
Interleukin-2
Alkylating Agents
Analgesics

ClinicalTrials.gov processed this record on November 20, 2014