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

Phase 1

Completed

• Conditions: Recurrent Grade 1 Follicular Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Waldenström Macroglobulinemia; B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Recurrent Mantle Cell Lymphoma
• Interventions: 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

• Registration Number: NCT00621452
• Lead Sponsor: Fred Hutchinson Cancer Center

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.

Study Timeline

• Study Start: 2007-08
• Study First Submitted: 2008-02-21
• Study First Submitted QC: 2008-02-21
• Study First Posted: 2008-02-22
• Primary Completion: 2014-01
• Status Verified: 2014-08
• Last Update Submitted: 2014-08-04
• Last Update Posted: 2014-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (autologous CD20 specific T-cells)	therapeutic autologous lymphocytes	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.
Treatment (autologous CD20 specific T-cells)	genetically engineered lymphocyte therapy	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.
Treatment (autologous CD20 specific T-cells)	flow cytometry	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.
Treatment (autologous CD20 specific T-cells)	polymerase chain reaction	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.
Treatment (autologous CD20 specific T-cells)	laboratory biomarker analysis	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.
Treatment (autologous CD20 specific T-cells)	gene rearrangement analysis	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.
Treatment (autologous CD20 specific T-cells)	aldesleukin	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.
Treatment (autologous CD20 specific T-cells)	bone marrow aspiration	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.
Treatment (autologous CD20 specific T-cells)	enzyme-linked immunosorbent assay	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.
Treatment (autologous CD20 specific T-cells)	lymph node biopsy	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.
Treatment (autologous CD20 specific T-cells)	cyclophosphamide	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.

Primary Outcome Measures

Name	Time	Method
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	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.

Secondary Outcome Measures

Name	Time	Method
Comparison of the percentages of CD20-specific T cells and malignant B cells present in the blood before and after each T cell infusion	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).
Immune response as assessed by ELISA and percent chromium release in cytotoxicity assays	Up to 12 months following treatment	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	Up to 1 year

Trial Locations

Locations (1)

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States