Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Vaccines made from gene-modified tumor cells may help the body build an effective immune response to kill tumor cells. Biological therapies, such as cyclophosphamide and trastuzumab, may increase the number of immune cells and make the immune response stronger. It is not yet known whether giving cyclophosphamide together with vaccine therapy is more effective with or without trastuzumab in treating patients with metastatic breast cancer. PURPOSE: This randomized phase II trial is studying the side effects of giving cyclophosphamide together with vaccine therapy and to see how well it works compared with giving cyclophosphamide and vaccine therapy together with trastuzumab in treating patients with metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary To evaluate the safety of cyclophosphamide-modulated vaccination with vs without trastuzumab in patients with breast cancer that does not overexpress HER-2/neu. To compare the clinical benefit of cyclophosphamide-modulated vaccination with vs without trastuzumab in these patients. To measure HER-2/neu-specific CD4+ and CD8+ T-cell immunity by delayed-type hypersensitivity (DTH) and ELISPOT. To measure the pharmacodynamics of CD4+CD25+ regulatory T cells by flow cytometry. Secondary To assess the impact of trastuzumab on immune priming in vivo by immunohistochemistry of vaccine-site biopsies at day +3 and day +7 of courses 1 and 3 on the two study arms, comparing cellular infiltrates to those seen in previous preclinical and clinical models. To measure hTERT-specific CD8+ T-cell immunity by ELISPOT. To characterize the peripheral-memory T-cell pool. Tertiary To determine baseline and change in vaccine site-draining lymph node immunohistology and gene expression profile. To develop the tandem tetramer/CD107a cytotoxicity assay for HER-2/neu-specific CD8+ T cells. To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months. Arm II: Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months. Skin punch and lymph node biopsies are collected at baseline and on days +3 and +7 of courses 1 and 3 for biomarker analysis. After completion of study treatment, patients are followed periodically.

Official Title
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A Randomized, Open-Label Comparative Study of Combination Therapy With Cyclophosphamide and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine With or Without Trastuzumab for the Treatment of Metastatic Breast Cancer That Does NOT Over-express HER-2/Neu

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: allogeneic GM-CSF-secreting breast cancer vaccine
* Biological: trastuzumab
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast Does not overexpress HER-2/neu, defined as FISH negative or 0, 1+, or 2+ by IHC Stage IV disease Must not be eligible for therapy of known curative potential for metastatic breast cancer Measurable or evaluable disease Stable CNS disease allowed provided that it's adequately treated and 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 Platelets > 100,000/mm^3 Serum bilirubin < 2.0 mg/dL (unless due to Gilbert syndrome) AST and ALT < 2 times upper limit of normal (ULN) Alkaline phosphatase < 5 times ULN Serum creatinine < 2.0 mg/dL Ejection fraction normal by MUGA OR ≥ 50% by echocardiogram Not pregnant or nursing Fertile patients must use effective contraception HIV negative Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed No prior or concurrent 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 Sjogren syndrome Sarcoidosis Other rheumatologic disease No other malignancies within the past 5 years, except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, superficial bladder cancer, or tamoxifen-related endometrial cancer that has been adequately treated No active major medical or psychosocial problems that could be complicated by study participation No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest No uncontrolled medical problems No evidence of active acute or chronic infection No known severe hypersensitivity to trastuzumab, except mild to moderate infusion reactions that are easily managed and do not recur No allergy to corn PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 28 days since prior and no other concurrent chemotherapy, radiation therapy, or biologic therapy (except trastuzumab) Concurrent endocrine therapy and supportive therapy with bisphosphonates allowed More than 28 days since prior and no other concurrent participation in an investigational new drug trial More than 28 days since prior and no other concurrent systemic oral steroids Topical, ocular, and nasal steroids allowed No prior vaccination with the allogeneic GM-CSF-secreting breast tumor vaccine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclophosphamide and Vaccine only<br>Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months. | Biological: allogeneic GM-CSF-secreting breast cancer vaccine<br>* Given intradermally<br>Drug: cyclophosphamide<br>* Given IV<br>|
| Experimental: Cyclophosphamide, Vaccine and Trastuzumab<br>Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months. | Biological: allogeneic GM-CSF-secreting breast cancer vaccine<br>* Given intradermally<br>Biological: trastuzumab<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as Assessed by Number of Grade 3 or 4 Adverse Events | Number of grade 3 or 4 nonhematologic toxicity (except alopecia), or any grade 4 hematologic toxicity as defined by NCI CTCAE v3.0 | 3 years | 
| Clinical Benefit (CB) as Assessed by Progression Free Survival at Six Months | Progression-free survival is measured as percentage of participants with stable disease or complete response, as defined by RECIST criteria, six months after receiving last vaccination. Progressive disease (PD) will be defined by the appearance of a new lesion, or by an increase of at least 20% in the sum of the longest diameter of target lesions, taking as a reference that smallest sum longest diameter recorded since the study intervention began. In the case of bone lesions, progressive disease will be established after eight weeks of increasing or new lesions if there is subjective progressive disease as noted by increasing bone pain or decreasing performance status. These observations must be present for at least two measurement periods separated by at least four weeks. | 6 months post-intervention | 
| HER-2/Neu-specific Immune Responses as Measured by Number of Participants With Positive for Delayed-type Hypersensitivity (DTH) Response |  | 3 years | 
| Pharmacodynamics of Peripheral CD4+CD25+ Regulatory T Cells |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Priming in In-vivo Vaccine-site Biopsies |  | 3 years | 
| Enumeration of CD8+ T Cells Specific for hTERT by ELISPOT |  | 3 years | 
| Characterization of the T-cell Memory Pool Pre- and Post-vaccination |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, male breast cancer