Vaccine Therapy With or Without Cyclophosphamide and Doxorubicin in Women With Stage IV Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Vaccines made from a person's tumor cells may make the body build an immune response to kill tumor cells. Drugs used in chemotherapy, such as cyclophosphamide and doxorubicin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining vaccine therapy with cyclophosphamide and doxorubicin may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of cyclophosphamide and doxorubicin when given with vaccine therapy in treating women with stage IV breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine the safety of vaccination comprising allogeneic sargramostim (GM-CSF)-secreting breast cancer cells with or without immunomodulation using cyclophosphamide and doxorubicin in women with stage IV breast cancer. Determine the doses of cyclophosphamide and doxorubicin that maximize vaccine-induced immunity, in terms of immune response to HER2/neu, in patients treated with these regimens. Compare in vivo immune response induced by these regimens, as measured by immunohistochemical analysis of vaccine site biopsies from these patients, with responses seen in prior preclinical and clinical studies. Secondary Determine the time to disease progression in patients treated with these regimens. OUTLINE: This is a dose-finding study. The first 6 patients receive 1 of 2 doses of vaccine comprising allogeneic sargramostim (GM-CSF)-secreting breast cancer cells intradermally (ID) on day 0. Subsequent patients receive cyclophosphamide IV on day -1, vaccine at the higher dose ID on day 0, and doxorubicin IV on day 7. Treatment in all patients repeats every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after the third course receive a fourth course of treatment at approximately 4 months after completion of the third course. Cohorts of 2-3 patients receive a fixed dose of vaccine in combination with escalating doses of doxorubicin and cyclophosphamide. Doses of cyclophosphamide and doxorubicin are escalated until an optimal dose of combination chemotherapy with a fixed dose of vaccine is achieved. Patients are followed at 1 month and 4 months after completion of study therapy and then annually thereafter. PROJECTED ACCRUAL: A total of 6-60 patients will be accrued for this study.

Official Title
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A Phase I Vaccine Safety and Chemotherapy Dose-Finding Trial of an Allogeneic GM-CSF-Secreting Breast Cancer Vaccine Given in a Specifically Timed Sequence With Immunomodulatory Doses of Cyclophosphamide and Doxorubicin

Conditions
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Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast Stage IV disease Stable disease for ≥ 28 days Measurable or evaluable disease OR no evidence of disease Not eligible for potentially curative therapy Adequately treated CNS metastases are allowed Hormone receptor status: Not specified HER-2/neu status: Not specified PATIENT CHARACTERISTICS: Age 18 and over Sex Female Menopausal status Not specified Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 Hepatic Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome) AST and ALT ≤ 2 times upper limit of normal (ULN) Alkaline phosphatase ≤ 5 times ULN Renal Creatinine < 2.0 mg/dL Cardiovascular Ejection fraction ≥ 45% by echocardiogram or MUGA Pulmonary Asthma or chronic obstructive pulmonary disease allowed provided daily systemic corticosteroid therapy is not required Immunologic No active autoimmune disease requiring systemic immunosuppressive therapy, including any of the following: Inflammatory bowel disease Systemic vasculitis Scleroderma Psoriasis Multiple sclerosis Hemolytic anemia Immune-mediated thrombocytopenia Rheumatoid arthritis Systemic lupus erythematosus Sjögren's syndrome Sarcoidosis Other rheumatologic disease HIV negative No active acute or chronic infection No allergy to corn Other No other malignancy within the past 5 years except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer No active major medical or psychosocial problem that would preclude study participation Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy More than 28 days since prior biologic therapy No other concurrent biologic therapy, including trastuzumab (Herceptin®) Chemotherapy Prior adjuvant chemotherapy allowed Prior doxorubicin and cyclophosphamide allowed Prior doxorubicin dose combined with planned study therapy dose must not exceed a lifetime cumulative dose of ≥ 450 mg/m^2 More than 28 days since prior systemic chemotherapy No other concurrent systemic chemotherapy Endocrine therapy More than 28 days since prior systemic corticosteroids Concurrent hormonal or endocrine therapy allowed No concurrent systemic corticosteroids Radiotherapy More than 28 days since prior radiotherapy No concurrent radiotherapy Surgery Not specified Other More than 28 days since prior participation in another investigational drug trial No other concurrent investigational drugs Concurrent bisphosphonates allowed

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

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: allogeneic GM-CSF-secreting breast cancer vaccine|The first three patients will receive a dose of 5 X 107 cells, and the next three will receive a dose of 5 X 108 cells. Then, if these two doses of vaccine alone are found to be safe, a fixed vaccine dose of 5 X 108 cells will be tested in combination with chemotherapy based on the safety of the allogeneic breast vaccine alone and the safety and bioactivity of a dose of 5 X 108 cells in the allogeneic pancreatic vaccine trial|
|Drug: cyclophosphamide|This trial will be a dose ranging study of a fixed sequence of drug doses in a three by three factorial matrix modeled after the theories of Plackett and Burman (Plackett et al., 1946), and is designed to determine the doses of CY and DOX that maximize the immunologic response to vaccination|
|Drug: doxorubicin hydrochloride|This trial will be a dose ranging study of a fixed sequence of drug doses in a three by three factorial matrix modeled after the theories of Plackett and Burman (Plackett et al., 1946), and is designed to determine the doses of CY and DOX that maximize the immunologic response to vaccination|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by history and phys. exam. at 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination |  | 4 years | 
| Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by CBC w/ differential at days 7, 14, 21, and 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination |  | 4 years | 
| Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by comprehensive metabolic panel at day 7 and 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination |  | 4 years | 
| Immune resp. of HER-2/neu by serum antibody titers, delayed hypersensitivity to HER-2/neu-derived peptides, and CD4+ T-cell resp. by ELISPOT at days 28-42 after each vaccination and days 56-84 after third vaccination |  | 4 years | 
| Immune responses by immunohistochemical analysis of vaccine site biopsies at days 3 and 7 after the first and third vaccinations |  | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to disease progression by history and physical examination, computed tomography, bone scans, and tumor markers as appropriate at days 28-42 after third and fourth vaccinations and days 56-84 after third vaccination |  | 4 years | 

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