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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

Primary Purpose

B-cell Chronic Lymphocytic Leukemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
therapeutic autologous lymphocytes
cyclophosphamide
aldesleukin
polymerase chain reaction
gene rearrangement analysis
lymph node biopsy
genetically engineered lymphocyte therapy
bone marrow aspiration
flow cytometry
laboratory biomarker analysis
enzyme-linked immunosorbent assay
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (autologous CD20 specific T-cells)

Arm Description

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.

Outcomes

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
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
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
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

Full Information

First Posted
February 21, 2008
Last Updated
August 4, 2014
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00621452
Brief Title
Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2014
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (autologous CD20 specific T-cells)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
therapeutic autologous lymphocytes
Other Intervention Name(s)
AL, Autologous Lymphocytes, autologous T cells
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
aldesleukin
Other Intervention Name(s)
IL-2, Proleukin, recombinant human interleukin-2, recombinant interleukin-2
Intervention Description
Given subcutaneously
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Other Intervention Name(s)
PCR
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
gene rearrangement analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
lymph node biopsy
Other Intervention Name(s)
Biopsy of Lymph Node
Intervention Description
Optional correlative studies
Intervention Type
Biological
Intervention Name(s)
genetically engineered lymphocyte therapy
Intervention Description
Receive genetically modified T cells
Intervention Type
Procedure
Intervention Name(s)
bone marrow aspiration
Intervention Description
Optional correlative studies
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
enzyme-linked immunosorbent assay
Other Intervention Name(s)
ELISA
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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
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.
Time Frame
Up to 2 years after final T cell infusion
Secondary Outcome Measure Information:
Title
Comparison of the percentages of CD20-specific T cells and malignant B cells present in the blood before and after each T cell infusion
Description
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).
Time Frame
Up to 4 weeks after the third infusion
Title
Immune response as assessed by ELISA and percent chromium release in cytotoxicity assays
Description
Means, medians and standard deviation (S.D.) of the Ab titers observed will be computed.
Time Frame
Up to 12 months following treatment
Title
Absolute numbers of T cells expressing the chimeric T Cell receptor (cTCR) per cubic uL of blood
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian Till
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22308288
Citation
Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012 Apr 26;119(17):3940-50. doi: 10.1182/blood-2011-10-387969. Epub 2012 Feb 3.
Results Reference
derived

Learn more about this trial

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

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