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

August 4, 2014 updated by: Fred Hutchinson Cancer Center

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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.
Up to 2 years after final T cell infusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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).
Up to 4 weeks after the third infusion
Immune response as assessed by ELISA and percent chromium release in cytotoxicity assays
Time Frame: Up to 12 months following treatment
Means, medians and standard deviation (S.D.) of the Ab titers observed will be computed.
Up to 12 months following treatment
Absolute numbers of T cells expressing the chimeric T Cell receptor (cTCR) per cubic uL of blood
Time Frame: Up to 1 year
Up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fred Hutchinson Cancer Center

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Brian Till, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2007

Primary Completion (Actual)

January 1, 2014

Study Registration Dates

First Submitted

February 21, 2008

First Submitted That Met QC Criteria

February 21, 2008

First Posted (Estimate)

February 22, 2008

Study Record Updates

Last Update Posted (Estimate)

August 6, 2014

Last Update Submitted That Met QC Criteria

August 4, 2014

Last Verified

August 1, 2014

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2154.00
  • NCI-2010-00416 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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