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Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung Cancer Previously Treated With HER-2/Neu Vaccine

Primary Purpose

HER2-positive Breast Cancer, Recurrent Breast Cancer, Recurrent Non-small Cell Lung Cancer

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ex vivo-expanded HER2-specific T cells
cyclophosphamide
denileukin diftitox
flow cytometry
immunoenzyme technique
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer

Eligibility Criteria

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

Inclusion Criteria: Patients with progressive HER2/neu overexpressing metastatic breast, ovarian, or non-small cell lung cancer not considered curable by conventional therapies, including trastuzumab Extra-skeletal disease that can be accurately measured >= 10 mm by standard imaging techniques that can include but not limited to computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) Skeletal or bone-only disease which is measurable by Fludeoxyglucose F 18 (FDG) PET imaging will also be allowed Patients with ovarian cancer may have measurable disease; however, their only indication of progression may be an abnormal CA-125 Patients must have documented HER-2/neu overexpression in their tumor (either primary or metastasis) as was required per the eligibility criteria of their original vaccination protocol Patients must have received HER2-specific vaccinations while enrolled on a HER2 vaccine protocol approved at the University of Washington Human Subjects Division Patients must have undergone leukapheresis after vaccination through a protocol approved at the University of Washington Human Subjects Division and have product stored for clinical use Subjects must have a Performance Status Score (Zubrod/Eastern Cooperative Oncology Group [ECOG] Scale) = 0 or 1 Patients can be currently receiving trastuzumab and/or lapatinib and/or hormonal therapy and/or bisphosphonate therapy Patients on trastuzumab and/or lapatinib must have adequate cardiac function as demonstrated by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) within 90 days of eligibility determination Patients must be off all immunosuppressive treatments, and/or systemic steroid therapy, for at least 14 days prior to initiation of study treatment Patients must be off chemotherapy and trastuzumab for at least 1 week prior to the first infusion of T cells Men and women of reproductive ability must agree to contraceptive use during the study and for one month after the final T cell infusion Patients with a history of brain metastases must have a stable head imaging study within 30 days of enrollment White blood cells (WBC) >= 3000/mm^3 Absolute neutrophil count (ANC) >= 1000/mm^3 Hemoglobin (Hgb) >= 10 mg/dl Platelets >= 75,000mm^3 Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 2.5 mg/dl Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 3 times ULN Exclusion Criteria: Concurrent enrollment in other treatment studies Patients with any of the following cardiac conditions: Symptomatic restrictive cardiomyopathy Unstable angina within the last 4 months prior to enrollment New York Heart Association functional class III-IV heart failure on active treatment Patients with any clinically significant autoimmune disease uncontrolled with treatment Pregnant or breast-feeding women Known history of hypersensitivity to diphtheria toxin or interleukin (IL)-2 (only for subjects enrolled in Group B)

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group A (cellular infusions after cyclophosphamide)

Group B (cellular infusions after ONTAK conditioning)

Arm Description

Patients receive low-dose cyclophosphamide IV on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20.

Patients receive denileukin diftitox IV over 1 hour on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20.

Outcomes

Primary Outcome Measures

Feasibility of expanding HER2 specific T cells ex vivo to achieve a target T cell expansion of 1x10^10 HER2 specific T cells
The procedure will be defined as feasible if the minimum target expansion of HER2 specific T cells is achieved in 2/3 expansions in 4/5 subjects within an arm.
Safety of infusing HER2 specific T cells
Toxicity grading will be evaluated according to the CTEP CTCAE v3.0 criteria. A specific dose of HER2 specific T cells will be defined as safe if 4 of 5 subjects in a study arm tolerate that dose without dose-limiting toxicity (DLT).

Secondary Outcome Measures

Number of patients in whom the precursor frequency of antigen specific T cells is increased by 10-fold over baseline within one week after the last infusion
Number of patients in whom an immune response is demonstrated if baseline immune response was below detection
HER2 specific CD4+ or CD8+ precursor frequencies as assessed by cytokine flow cytometry or ELISPOT
Anti-tumor effects of HER2 specific T cells as assessed by RECIST criteria
Persistence of T cell immune augmentation in vivo after adoptive transfer of HER2 specific T cells

Full Information

First Posted
September 13, 2005
Last Updated
November 7, 2014
Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00228358
Brief Title
Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung Cancer Previously Treated With HER-2/Neu Vaccine
Official Title
A Phase I Study of Infusion of HER-2/Neu Specific T Cells in Patients With Advanced Stage HER-2/Neu Expressing Cancers Who Have Received a HER-2/Neu Vaccine
Study Type
Interventional

2. Study Status

Record Verification Date
November 2014
Overall Recruitment Status
Completed
Study Start Date
June 2003 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I trial studies the safety and the ability to expand laboratory-treated T cells when given together with cyclophosphamide or denileukin diftitox in treating patients with human epidermal growth factor receptor (HER)-2/neu overexpressing metastatic breast cancer, ovarian cancer, or non-small cell lung cancer previously treated with HER-2/neu vaccine. Laboratory-expanded T cells may help the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapy, such as denileukin diftitox, may stimulate the immune system in different ways and stop tumor cells from growing. Giving laboratory-treated T cells together with cyclophosphamide or denileukin diftitox may allow the immune system to kill more tumor cells
Detailed Description
PRIMARY OBJECTIVES: I. To assess the feasibility of expanding HER2 specific T cells ex vivo for infusion into subjects who have advanced HER2 overexpressing cancer. II. To assess the toxicity associated with infusing autologous HER2 specific T cells into patients using either a single dose of cyclophosphamide or ONTAK (denileukin diftitox) prior to T cell infusion. SECONDARY OBJECTIVES: I. To investigate to what extent HER2 specific T cell immunity can be boosted in individuals treated with a single dose of cyclophosphamide of ONTAK followed by infusion of autologous HER2 specific T cells. II. To investigate the potential anti-tumor effects of HER2 specific T cells in patients with HER2 overexpressing advanced-stage cancers. III. To evaluate how long tumor antigen specific T cell immune augmentation persists in vivo after a single dose of cyclophosphamide or ONTAK followed by infusion of autologous HER2 specific T cells. OUTLINE: This is a dose-escalation study of ex vivo-expanded HER2-specific T cells. Patients are assigned to 1 of 2 treatment groups. GROUP A: Patients receive low-dose cyclophosphamide intravenously (IV) on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20. GROUP B: Patients receive ONTAK (denileukin diftitox) IV over 1 hour on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20. After completion of study treatment, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HER2-positive Breast Cancer, Recurrent Breast Cancer, Recurrent Non-small Cell Lung Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Ovarian Germ Cell Tumor, Stage IV Breast Cancer, Stage IV Non-small Cell Lung Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Ovarian Germ Cell Tumor

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Group A (cellular infusions after cyclophosphamide)
Arm Type
Experimental
Arm Description
Patients receive low-dose cyclophosphamide IV on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20.
Arm Title
Group B (cellular infusions after ONTAK conditioning)
Arm Type
Experimental
Arm Description
Patients receive denileukin diftitox IV over 1 hour on day -1 and 3 escalating doses of autologous ex vivo-expanded HER2-specific T cells IV over 30 minutes on days 1, 10, and 20.
Intervention Type
Drug
Intervention Name(s)
ex vivo-expanded HER2-specific T cells
Intervention Description
Laboratory-expanded T cells, 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)
denileukin diftitox
Other Intervention Name(s)
DAB389 interleukin-2, DAB389 interleukin-2 immunotoxin, DAB389-IL2, DABIL2
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Intracellular cytokine staining (correlative study)
Intervention Type
Other
Intervention Name(s)
immunoenzyme technique
Other Intervention Name(s)
immunoenzyme techniques
Intervention Description
ELIspot assay (correlative study)
Primary Outcome Measure Information:
Title
Feasibility of expanding HER2 specific T cells ex vivo to achieve a target T cell expansion of 1x10^10 HER2 specific T cells
Description
The procedure will be defined as feasible if the minimum target expansion of HER2 specific T cells is achieved in 2/3 expansions in 4/5 subjects within an arm.
Time Frame
Up to day 40
Title
Safety of infusing HER2 specific T cells
Description
Toxicity grading will be evaluated according to the CTEP CTCAE v3.0 criteria. A specific dose of HER2 specific T cells will be defined as safe if 4 of 5 subjects in a study arm tolerate that dose without dose-limiting toxicity (DLT).
Time Frame
Up to day 40
Secondary Outcome Measure Information:
Title
Number of patients in whom the precursor frequency of antigen specific T cells is increased by 10-fold over baseline within one week after the last infusion
Time Frame
Up to one week following last infusion
Title
Number of patients in whom an immune response is demonstrated if baseline immune response was below detection
Time Frame
Up to one week following last infusion
Title
HER2 specific CD4+ or CD8+ precursor frequencies as assessed by cytokine flow cytometry or ELISPOT
Time Frame
Up to 1 year following last infusion
Title
Anti-tumor effects of HER2 specific T cells as assessed by RECIST criteria
Time Frame
Day 40
Title
Persistence of T cell immune augmentation in vivo after adoptive transfer of HER2 specific T cells
Time Frame
Up to 1 year following last infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with progressive HER2/neu overexpressing metastatic breast, ovarian, or non-small cell lung cancer not considered curable by conventional therapies, including trastuzumab Extra-skeletal disease that can be accurately measured >= 10 mm by standard imaging techniques that can include but not limited to computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) Skeletal or bone-only disease which is measurable by Fludeoxyglucose F 18 (FDG) PET imaging will also be allowed Patients with ovarian cancer may have measurable disease; however, their only indication of progression may be an abnormal CA-125 Patients must have documented HER-2/neu overexpression in their tumor (either primary or metastasis) as was required per the eligibility criteria of their original vaccination protocol Patients must have received HER2-specific vaccinations while enrolled on a HER2 vaccine protocol approved at the University of Washington Human Subjects Division Patients must have undergone leukapheresis after vaccination through a protocol approved at the University of Washington Human Subjects Division and have product stored for clinical use Subjects must have a Performance Status Score (Zubrod/Eastern Cooperative Oncology Group [ECOG] Scale) = 0 or 1 Patients can be currently receiving trastuzumab and/or lapatinib and/or hormonal therapy and/or bisphosphonate therapy Patients on trastuzumab and/or lapatinib must have adequate cardiac function as demonstrated by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) within 90 days of eligibility determination Patients must be off all immunosuppressive treatments, and/or systemic steroid therapy, for at least 14 days prior to initiation of study treatment Patients must be off chemotherapy and trastuzumab for at least 1 week prior to the first infusion of T cells Men and women of reproductive ability must agree to contraceptive use during the study and for one month after the final T cell infusion Patients with a history of brain metastases must have a stable head imaging study within 30 days of enrollment White blood cells (WBC) >= 3000/mm^3 Absolute neutrophil count (ANC) >= 1000/mm^3 Hemoglobin (Hgb) >= 10 mg/dl Platelets >= 75,000mm^3 Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 2.5 mg/dl Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 3 times ULN Exclusion Criteria: Concurrent enrollment in other treatment studies Patients with any of the following cardiac conditions: Symptomatic restrictive cardiomyopathy Unstable angina within the last 4 months prior to enrollment New York Heart Association functional class III-IV heart failure on active treatment Patients with any clinically significant autoimmune disease uncontrolled with treatment Pregnant or breast-feeding women Known history of hypersensitivity to diphtheria toxin or interleukin (IL)-2 (only for subjects enrolled in Group B)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary Disis
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

Learn more about this trial

Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung Cancer Previously Treated With HER-2/Neu Vaccine

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