Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for the Treatment of HER-2/Neu-Overexpressing Metastatic Breast Cancer
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Intervention: Allogeneic GM-CSF-secreting breast cancer vaccine; Trastuzumab; Cyclophosphamide
Intervention description: the vaccine containing a mixture of two GM-CSF-secreting allogeneic breast cancer cell lines (two parts 2T47D-V and one part 3SKBR3-7 mixed in a fixed dose of 5 X 108 cells for each patient and each vaccination cycle) on day 0.; Trastuzumab is a humanized monoclonal antibody specific for the extracellular domain of HER-2/neu that is now one component of the standard of care for both early and late stage HER-2/neu-overexpressing breast cancers. It exerts a pleiotropic antitumor effect by multiple mechanisms. The antibody decreases heterodimer formation with other members of the epidermal growth factor receptor (EGFR) family, thereby indirectly inhibiting signaling through the Ras/Raf/mitogen-activated protein kinases (MAPK) and Phosphatidylinositol 3-kinase(PI3K)/protein kinase B (Akt) pathways. It also inhibits tumor neovascularization, and augments apoptosis both in vitro and in vivo. Trastuzumab prevents cleavage of the extracellular domain of HER-2/neu, thus abrogating the constitutive activation of the remaining membrane-associated intracellular domain.; The doses of Cyclophosphamide are based on previously reported clinical experience as well as our own preclinical data demonstrating augmented vaccine efficacy with CY-modulated vaccination. In particular, 300 mg/m2
Intervention MeSH terms: Cyclophosphamide; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Stage IV HER-2/neu overexpressing breast cancer

Summary:

      This is a feasibility study to examine combination therapy with Trastuzumab (T),
      Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine in
      patients with Stage IV HER-2/neu-overexpressing breast cancer. The main purposes of this
      study are to test the safety, clinical benefit, and bioactivity of vaccine therapy in
      combination with Cyclophosphamide and Trastuzumab in patients with HER-2/neu-overexpressing
      Stage IV breast cancer. This study will also to test whether the Cyclophosphamide can
      eliminate the suppressive influence of regulatory T cells, and whether Trastuzumab can
      increase antigen processing and presentation. These drug activities may make the immune
      system react better and enhance the effects of the vaccine in treating breast cancer. The
      vaccine consists of two irradiated allogeneic mammary carcinoma cell lines genetically
      modified to secrete human granulocyte-macrophage colony stimulating factor (GM-CSF). This
      open label, single arm study is designed to recruit up to 40 subjects to identify 20 research
      subjects with HER-2/neu-overexpressing Stage IV breast cancer eligible for study treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the
             breast; this is defined as HER-2+ by immunohistochemistry (IHC) 3+ staining or
             Fluorescence In-Situ Hybridization (FISH). Prior adjuvant Trastuzumab therapy is
             permitted. Patients must not be eligible for therapy of known curative potential for
             metastatic breast cancer if it is identified during the course of the study.

          2. Patients may have measurable or evaluable disease.

          3. Stable central nervous system (CNS) disease that has been adequately treated and is
             not under active treatment allowed.

          4. Age 18 years or older.

          5. Able to give informed consent.

          6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or
             1.

          7. No systemic oral steroids administered within 28 days prior to initiating treatment on
             protocol. Topical, ocular, and nasal steroids are allowed, as are those applied to
             mucus membranes.

          8. No prior or currently active autoimmune disease requiring management with systemic
             immunosuppression. This includes inflammatory bowel disease, systemic vasculitis,
             scleroderma, psoriasis, multiple sclerosis, hemolytic anemia or immune-mediated
             thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's
             syndrome, sarcoidosis, or other rheumatologic disease. Asthma or chronic obstructive
             pulmonary disease that does not require daily systemic corticosteroids is acceptable.

          9. Not pregnant, and on appropriate birth control if of child-bearing potential.

         10. No history of other malignancies within the prior five years (excluding a history of
             carcinoma in situ of the cervix, superficial non-melanoma skin cancer, and superficial
             bladder cancer).

         11. Adequate bone marrow reserve with absolute neutrophil count (ANC) > 1000 and platelets
             > 100,000.

         12. Adequate renal function with serum creatinine < 2.0.

         13. Adequate hepatic reserve with serum bilirubin < 2.0, aspartate transaminase (AST) and
             alanine aminotransferase (ALT) < 2X the upper limit of normal, and alkaline
             phosphatase < 5X the upper limit of normal. Serum bilirubin > 2.0 is acceptable in the
             setting of known Gilbert's syndrome.

         14. Adequate cardiac reserve with a cardiac ejection fraction within the lower limit of
             facility normal by MUGA, or 45% by echocardiogram.

         15. No active major medical or psychosocial problems that could be complicated by study
             participation.

         16. HIV negative.

        Exclusion Criteria:

          1. No histologic documentation of breast adenocarcinoma.

          2. Breast adenocarcinoma that is not amplified for HER-2/neu gene expression by at least
             2-fold by FISH analysis, or that is less than IHC 3+ when FISH negative.

          3. Cardiac dysfunction documented by an ejection fraction less than the lower limit of
             the facility normal by multi-gated acquisition (MUGA) scan, or 45% by echocardiogram.

          4. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs
             resulting in dyspnea at rest.

          5. History of autoimmune disease as detailed above.

          6. Systemic oral corticosteroid treatment within 28 days prior to initiating treatment on
             study.

          7. Uncontrolled medical problems.

          8. Evidence of active acute or chronic infection.

          9. Chemotherapy, radiation therapy, or biologic therapy (except Trastuzumab) within 28
             days prior to initiating treatment on study. Hormonal therapy and supportive therapy
             with bisphosphonates will be allowed.

         10. Participation in an investigational new drug trial within 28 days prior to initiating
             treatment on study.

         11. Pregnant or breast feeding.

         12. Hepatic, renal, or bone marrow dysfunction as detailed above.

         13. Concurrent malignancy or history of other malignancy within the last five years except
             as noted above.

         14. Corn allergy.

         15. Known severe hypersensitivity to Trastuzumab (excluding mild to moderate infusion
             reactions that are easily managed and do not recur).