Trial Information

Phase I-II Study of Combination Immunotherapy for the Generation of HER-2/Neu (HER2) Specific Cytotoxic T Cells (CTL) in Vivo

Study Population:

Patients with HER2 overexpressing Stage IV breast cancer who are on maintenance trastuzumab
alone after being treated with chemotherapy and trastuzumab until there is no evidence of
disease (NED) or stable disease. Stage IV HER2 overexpressing ovarian cancer patients who
are on maintenance trastuzumab alone or after being treated with chemotherapy and
trastuzumab until there is no evidence of disease (NED) or stable disease.

Patients must be HLA-A2.

Rationale:

Data from tumor vaccine studies now indicate there might be survival advantages for patients
who have received tumor-antigen specific vaccinations. Our group has demonstrated a
potential survival advantage for patients with advanced stage HER2 overexpressing breast
cancer immunized with a HER2 peptide based vaccine after being treated to maximal response
or complete remission with standard therapy. Recent studies have demonstrated that
"sensitization" of HER2 overexpressing tumor cells with trastuzumab, in vitro, will enhance
the function of CTL specific for HER2. Theoretically, the mechanism of trastuzumab's
enhancement of a HER2 specific CTL response might be the internalization of the HER2
receptor, degradation of the HER2 protein, and increased MHC-peptide presentation with a
resultant increase in CD8+ HER2 specific CTL function. Thus, combination of trastuzumab
with HER2 peptide based vaccine designed to elicit CTL in the context of HLA-A2 may even
further enhance the generation of a HER2 specific CTL response and potentially translate
into improved survival for advanced stage breast and ovarian cancer patients when used in
the adjuvant setting.

This proposal outlines a clinical trial designed to utilize the potential synergistic effect
between trastuzumab and a HER2 CTL generating peptide based vaccine (HER2 CTL vaccine) in
order to increase CTL precursor frequencies that target HER2 specific epitopes. Patients
will be treated to NED or stable disease with chemotherapy and trastuzumab or trastuzumab
alone and while on maintenance trastuzumab receive vaccinations with a HER2 CTL vaccine.

Objectives

Primary:

1. To evaluate the safety of administering a HER2 CTL peptide-based vaccine to Stage IV
breast and ovarian cancer patients receiving maintenance trastuzumab.

2. To quantify and characterize antigen specific T cells directed against HER2 in PBMC of
patients after vaccination with a HER CTL peptide-based vaccine administered while
receiving maintenance trastuzumab.

Secondary:

1. To evaluate overall survival (OS) in Stage IV breast cancer patients who complete a
vaccination series with a HER2 CTL peptide-based vaccine while receiving maintenance
trastuzumab.

Study Design:

This will be a single arm phase I-II single institution clinical trial in patients with HER2
overexpressing Stage IV breast and ovarian cancer who are on maintenance trastuzumab alone
after being treated with chemotherapy and trastuzumab or trastuzumab alone to NED or stable
disease. Patients will receive a monthly vaccination for 6 months with a HER2 CTL
peptide-based vaccine.

Number of Patients:

Twenty subjects will be enrolled. This will provide statistically adequate numbers of
subjects for gathering (1) safety data and (2) immunologic response data.

Outcome Measures

Primary Endpoints:

1. Safety will be assessed using NCI common toxicity criteria.

2. Immune response will be defined by cytokine flow cytometry (CFC). Specifically, a
positive immune response will be defined as a post-vaccination HER2 antigen specific
CD8 or CD4 precursor frequency measured by CFC of less than 1:20,000. For subjects who
have measurable precursors by CFC at baseline, a positive response will be defined as a
2-fold increase in either T cell subset after vaccination.

HLA-A2 MHC tetramer analysis will be used to demonstrate the specificity of the T cells for
the HER2 HLA-A2 defined epitopes. IFN-gamma secreting PBMC precursor frequency will also be
measured by ELIspot in order to determine the development of lower precursor frequencies not
detected by CFC. ELIspot measurements will not define response.

Secondary Endpoints:

1. Overall survival for all patients will be followed. Survival for the Stage IV breast
cancer patients will be compared to historical control. This study will not enroll
sufficient numbers of subjects to give statistical power to this endpoint. However, a large
difference observed between the treatment group and historical control would give additional
impetus for a phase II study of efficacy. Although the study will enroll both breast and
ovarian cancer patients, from our extensive experience in combined breast and ovarian cancer
vaccine studies for HER2, we anticipate approximately 80% of the subjects enrolled will be
Stage IV breast cancer patients.