Trastuzumab, Cyclophosphamide, and Vaccine Therapy in Treating Patients With High-Risk or Metastatic Breast Cancer

Tracking Information
First Submitted Date ICMJE	February 18, 2009
First Posted Date ICMJE	February 19, 2009
Last Update Posted Date	May 29, 2013
Study Start Date ICMJE	December 2008
Estimated Primary Completion Date	June 2013 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 21, 2011)	Safety (local and systemic toxicity) as assessed by NCI CTCAE v3.0 [ Time Frame: 4 years ]; Immunologic response (HER2/neu-specific immune response and delayed-type hypersensitivity response to HER2/neu-derived peptides) [ Time Frame: 4 years ]
Original Primary Outcome Measures ICMJE; (submitted: February 18, 2009)	Safety (local and systemic toxicity) as assessed by NCI CTCAE v3.0; Immunologic response (HER2/neu-specific immune response and delayed-type hypersensitivity response to HER2/neu-derived peptides)
Change History	Complete list of historical versions of study NCT00847171 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 21, 2011)	Clinical benefit as assessed by rate of progression-free survival [ Time Frame: 4 years ]
Original Secondary Outcome Measures ICMJE; (submitted: February 18, 2009)	Clinical benefit as assessed by rate of progression-free survival
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Trastuzumab, Cyclophosphamide, and Vaccine Therapy in Treating Patients With High-Risk or Metastatic Breast Cancer
Official Title ICMJE	A Safety and Bioactivity Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-Secreting Breast Tumor Vaccine for the Treatment of Patients With High Risk/ Metastatic HER-2/Neu- Overexpressing Breast Cancer With No Evidence of Disease
Brief Summary	RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. 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. Vaccines made from gene-modified tumor cells may help the body build an immune response to kill tumor cells. Giving trastuzumab together with cyclophosphamide and vaccine therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects of giving trastuzumab together with cyclophosphamide and vaccine therapy in treating patients with high-risk or metastatic breast cancer.
Detailed Description	OBJECTIVES: Primary; To evaluate the safety of allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine in combination with trastuzumab (Herceptin®) and cyclophosphamide in patients with high-risk or metastatic HER2/neu-overexpressing breast cancer.; To measure the HER2/neu-specific CD4+ T-cell response by delayed-type hypersensitivity.; To measure the magnitude of HER2/neu-specific CD8+ T-cell responses by ELISPOT. Secondary; To assess the impact of trastuzumab on immune priming in vivo by IHC.; To measure the impact of cyclophosphamide pretreatment on CD4+CD25+ regulatory T cells by flow cytometry.; To determine the time to disease progression. Tertiary; To develop the tandem tetramer/CD107a cytotoxicity assay for HER2/neu-specific CD8+ T cells.; To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination. OUTLINE: Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day -1 of the first course of vaccination and continuing until the completion of the last course of vaccination. Patients also receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine intradermally on day 0. Treatment with cyclophosphamide and the vaccine repeats every 27-42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth course of cyclophosphamide and vaccine approximately 6-8 months after the first course. Patients undergo delayed-type hypersensitivity testing and blood sample collection at baseline and periodically during study for immunologic laboratory studies. Blood samples are analyzed for serum GM-CSF levels by pharmacokinetic studies and for immune monitoring by ELISPOT and flow cytometry. Skin punch biopsies are also performed periodically and analyzed by IHC. After completion of study treatment, patients are followed periodically.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Breast Cancer
Intervention ICMJE	Biological: allogeneic GM-CSF-secreting breast cancer vaccine Day 0 : Allogeneic GM-CSF-secreting Breast Cancer Vaccine administered as: 12 intradermal injections of a divided total dose of 5 x108 cells.; Biological: trastuzumab Patient HAS received prior Trastuzumab within the last two weeks, give Trastuzumab 2 mg/kg weekly on Day -1 for 5 weeks. Patient has NOT received Trastuzumab within the last two weeks, give On Cycle 1, Day -1 ONLY, Loading dose 4 mg/kg Other Name: Herceptin; Drug: cyclophosphamide Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide. Other Name: Cytoxan; Other: flow cytometry Samples will be analyzed by flow cytometry using Cell Quest software; Other: immunoenzyme technique; Other: immunohistochemistry staining method Measuring Immune Priming In Vivo By Vaccine Site Biopsies; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: biopsy skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only
Study Arms	Not Provided
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Unknown status
Estimated Enrollment ICMJE; (submitted: February 18, 2009)	20
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	June 2013
Estimated Primary Completion Date	June 2013 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast, meeting one of the following criteria: Metastatic disease High-risk disease, defined as early-stage disease with pathologic involvement of locoregional lymph nodes Patients who are/will be receiving standard adjuvant trastuzumab [Herceptin®] for high-risk disease will participate in this study during the single-agent trastuzumab portion of their therapy; No clinical or radiographical evidence of active disease; Not eligible for therapy of known curative potential for metastatic breast cancer; HER2/neu-overexpressing disease, defined as HER2/neu positive by IHC 3+ staining or by FISH+ amplification; Stable CNS disease allowed provided it has been adequately treated and is not under active treatment; Hormone receptor status not specified PATIENT CHARACTERISTICS: Menopausal status not specified; ECOG performance status 0-1; ANC > 1,000/mm^3; Platelet count > 100,000/mm^3; Serum creatinine < 2.0 mg/dL; Serum bilirubin ≤ 2.0 mg/dL (unless elevation is due to known Gilbert's syndrome); AST/ALT ≤ 2 times upper limit of normal (ULN); Alkaline phosphatase ≤ 5 times ULN; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception; Cardiac ejection fraction normal by MUGA OR ≥ 45% by ECHO; No other malignancies within the past 5 years, except for carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer; No prior or currently active autoimmune disease* requiring management with systemic immunosuppression, including any of the following: Inflammatory bowel disease Systemic vasculitis Scleroderma Psoriasis Multiple sclerosis Hemolytic anemia or immune-mediated thrombocytopenia Rheumatoid arthritis Systemic lupus erythematosus Sjögren syndrome Sarcoidosis Other rheumatologic disease; No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest; HIV-negative; No evidence of active acute or chronic infection; No uncontrolled medical problems; No active major medical or psychosocial problems that could be complicated by study participation; No corn allergy; No known severe hypersensitivity to trastuzumab (except for mild to moderate infusion reactions that are easily managed and do not recur) NOTE: *Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed PRIOR CONCURRENT THERAPY: Any number of prior chemotherapy regimens for metastatic breast cancer allowed; Prior or concurrent trastuzumab in the adjuvant or metastatic setting allowed; More than 28 days since prior and no concurrent systemic oral steroids Topical, ocular, or nasal steroids allowed; More than 28 days since prior and no concurrent chemotherapy, radiotherapy, or biologic therapy (except trastuzumab); More than 28 days since prior and no concurrent participation in another investigational clinical trial involving a new drug; Concurrent endocrine therapy or bisphosphonates allowed
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00847171
Other Study ID Numbers ICMJE	J0885 CDR0000634155; P30CA006973 ( U.S. NIH Grant/Contract ); JHOC-NA_00021048; JHOC-J0885
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Sidney Kimmel Comprehensive Cancer Center
Study Sponsor ICMJE	Sidney Kimmel Comprehensive Cancer Center
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Principal Investigator: Leisha A. Emens, MD, PhD Sidney Kimmel Comprehensive Cancer Center
PRS Account	Sidney Kimmel Comprehensive Cancer Center
Verification Date	May 2013
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP