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 - Full Text View

Sponsor:	Fred Hutchinson Cancer Research Center
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:	NCT00228358

Purpose

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

Condition	Intervention	Phase
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	Drug: ex vivo-expanded HER2-specific T cells Drug: cyclophosphamide Biological: denileukin diftitox Other: flow cytometry Other: immunoenzyme technique	Phase I

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

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Lung Cancer Ovarian Cancer

Drug Information available for: Cyclophosphamide Interleukin-2 Denileukin diftitox

U.S. FDA Resources

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

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 [ Time Frame: Baseline and day 40 ] [ Designated as safety issue: No ]
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 [ Time Frame: Day 40 ] [ Designated as safety issue: Yes ]
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 [ Time Frame: Baseline and one week following last infusion ] [ Designated as safety issue: No ]
Number of patients in whom an immune response is demonstrated if baseline immune response was below detection [ Time Frame: Baseline and one week following last infusion ] [ Designated as safety issue: No ]
HER2 specific CD4+ or CD8+ precursor frequencies as assessed by cytokine flow cytometry or ELISPOT [ Time Frame: Baseline and day 40 ] [ Designated as safety issue: No ]
Anti-tumor effects of HER2 specific T cells as assessed by RECIST criteria [ Time Frame: Day 40 ] [ Designated as safety issue: No ]
Persistence of T cell immune augmentation in vivo after adoptive transfer of HER2 specific T cells [ Time Frame: Every 2 months for 1 year following last infusion ] [ Designated as safety issue: No ]

Estimated Enrollment:	10
Study Start Date:	June 2003
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Group A (cellular infusions after cyclophosphamide) 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.	Drug: ex vivo-expanded HER2-specific T cells Laboratory-expanded T cells, given IV Drug: cyclophosphamide Given IV Other Names: Cytoxan Ciclofosfamide Claphene Other: flow cytometry Intracellular cytokine staining (correlative study) Other: immunoenzyme technique ELIspot assay (correlative study) Other Name: immunoenzyme techniques
Experimental: Group B (cellular infusions after ONTAK conditioning) 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.	Drug: ex vivo-expanded HER2-specific T cells Laboratory-expanded T cells, given IV Biological: denileukin diftitox Given IV Other Names: DAB389 interleukin-2 DAB389 interleukin-2 immunotoxin DAB389-IL2 DABIL2 Other: flow cytometry Intracellular cytokine staining (correlative study) Other: immunoenzyme technique ELIspot assay (correlative study) Other Name: immunoenzyme techniques

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 (denileukin diftitox) 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 (denileukin diftitox) 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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
- Extraskeletal 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
Age > 18 years
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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00228358

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

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Mary Disis

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

More Information

No publications provided

Responsible Party:	Disis, Mary, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
ClinicalTrials.gov Identifier:	NCT00228358 History of Changes
Other Study ID Numbers:	6223, NCI-2009-01547
Study First Received:	September 13, 2005
Last Updated:	November 2, 2011
Health Authority:	United States: Federal Government; United States: Food and Drug Administration

Additional relevant MeSH terms:

Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasms, Germ Cell and Embryonal
Germinoma
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms

Lung Diseases
Respiratory Tract Diseases
Neoplasms by Histologic Type
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Cyclophosphamide
Denileukin diftitox
Interleukin-2
Immunosuppressive Agents

ClinicalTrials.gov processed this record on February 02, 2012