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Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for the Treatment of HER-2/Neu-Overexpressing Metastatic Breast Cancer

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ClinicalTrials.gov Identifier: NCT00399529
Recruitment Status : Completed
First Posted : November 15, 2006
Last Update Posted : December 13, 2012
Information provided by (Responsible Party):

Study Description
Brief 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.

Condition or disease Intervention/treatment Phase
Breast Neoplasms Biological: Allogeneic GM-CSF-secreting breast cancer vaccine Drug: Trastuzumab Drug: Cyclophosphamide Phase 2

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Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for HER-2/Neu-Overexpressing Metastatic Breast Cancer.
Study Start Date : September 2006
Primary Completion Date : February 2010
Study Completion Date : February 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Allo GM-CSF-secreting vaccine, Trastuzumab, Cyclophosphamide

Allogeneic GM-CSF-secreting breast cancer vaccine : 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 10^8 cells for each patient and each vaccination cycle) given intradermally every 4-6 weeks for 3 cycles and then a 4th dose given 6-8 months after beginning the study.

Trastuzumab : An initial loading dose of 4 mg/kg for participants beginning treatment with Trastuzumab, otherwise 2 mg/kg given every week intravenously

Cyclophosphamide : 300 mg/m^2 given intravenously every 4-6 weeks for 3 cycles and then once 6-8 months after beginning the study

Biological: Allogeneic GM-CSF-secreting breast cancer vaccine
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.
Other Names:
  • two parts 2T47D-V
  • one part 3SKBR3-7
Drug: Trastuzumab
Trastuzumab is a humanized monoclonal antibody specific for the extracellular domain of HER-2/neu (Carter et al., 1992) 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 (Emens, 2005). The antibody decreases heterodimer formation with other members of the EGFR family, thereby indirectly inhibiting signaling through the ras/Raf/MAPK and PI3K/Akt pathways (Arteaga, 2003). It also inhibits tumor neovascularization (Izumi et al., 2002), and augments apoptosis both in vitro and in vivo (Lee et al., 2002; Chang et al., 2003). Trastuzumab prevents cleavage of the extracellular domain of HER-2/neu, thus abrogating the constitutive activation of the remaining membrane-associated intracellular domain.
Other Name: Herceptin
Drug: Cyclophosphamide
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
Other Name: Cytoxan

Outcome Measures

Primary Outcome Measures :
  1. Safety will be evaluated by assessing toxicity related to the vaccine, CY, Trastuzumab, cardiac dysfunction, and the potential induction of autoimmunity. [ Time Frame: Until 30 days after intervention ]
  2. Clinical benefit will be assessed by re-evaluating disease status with tumor markers and RECIST criteria, or with full evaluation upon the development of new symptoms. [ Time Frame: Until 30 days after intervention ]

Secondary Outcome Measures :
  1. Immunological response [ Time Frame: Until 30 days after intervention ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the breast; this is defined as HER-2+ by IHC 3+ staining or 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 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 ANC > 1000 and platelets > 100,000.
  12. Adequate renal function with serum creatinine < 2.0.
  13. Adequate hepatic reserve with serum bilirubin < 2.0, AST/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).
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00399529

United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
American Cancer Society, Inc.
Avon Foundation
Cancer Treatment Research Foundation
The Commonwealth Fund
United States Department of Defense
Genentech, Inc.
Principal Investigator: Leisha A Emens, M.D.,Ph.D. Johns Hopkins University
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00399529     History of Changes
Obsolete Identifiers: NCT00397371
Other Study ID Numbers: J05118
RAC 0605-778
First Posted: November 15, 2006    Key Record Dates
Last Update Posted: December 13, 2012
Last Verified: December 2012

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Stage IV HER-2/neu overexpressing breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists