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


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Breast Cancer

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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.


Inclusion Criteria:



1. Subjects must have either Stage IV breast or ovarian cancer in remission or with
stable disease on trastuzumab monotherapy.

2. HER2 overexpression by immunohistocytochemistry (IHC) of 2+ or 3+, in the primary
tumor or metastasis. If overexpression is 2+ by IHC, then patients must have HER2
gene amplification documented by FISH.

3. Subjects must be HLA-A2 positive.

4. Eligible subjects must have completed appropriate treatment for their primary disease
and be off cytotoxic chemotherapy and any immunosuppressive agents such as systemic
steroids for at least 30 days prior to enrollment. Patients should continue
trastuzumab monotherapy throughout the course of this protocol. Concurrent hormonal
and biphosphonate therapies are allowed.

5. Subjects must have an ECOG Performance Status Score = 0 or 1 (Appendix A)

6. Male subjects must agree to contraceptive use during the study period (7 months) and
non-menopausal female subjects must agree to contraception for the remainder of their
childbearing years. (HER2 is overexpressed in normal fetal tissues. Therefore,
induction of long-term immunity to overexpressed HER2 could affect the viability of a
future fetus.)

7. Subjects must have a hematocrit greater than 30, a platelet count greater than
100,000, and a WBC greater than 3000/┬Ál. Laboratory tests should be performed within
60 days of enrollment.

8. Age older than18 years

9. Stable creatinine less than 2.0mg/dL, or creatinine clearance greater than 60ml/min.
Laboratory tests should be performed within 60 days of enrollment.

10. Serum bilirubin less than 1.5 mg/dl. Laboratory tests should be performed within 60
days of enrollment.

11. SGOT less than 2x ULN. Laboratory tests should be performed within 60 days of
enrollment.

12. Subjects must have recovered from major infections and/or surgical procedures and, in
the opinion of the investigator, not have a significant active concurrent medical
illness precluding protocol treatment or survival.

13. Patients must have a baseline LVEF measured by MUGA equal to or greater than the
lower limit of normal for the radiology facility and if there are two consecutive
MUGAS performed while on trastuzumab from the same radiology facility, there can not
be a decrease in LVEF of greater than 15% from the original MUGA scan.

Exclusion Criteria:

1. Subjects cannot be simultaneously enrolled on other treatment studies.

2. Any contraindication to receiving GM-CSF based vaccine products.

3. Cardiac disease, specifically restrictive cardiomyopathy, unstable angina within the
last 6 months prior to enrollment, New York Heart Association functional class III-IV
heart failure on active treatment with normalized LVEF on therapy, and symptomatic
pericardial effusion.

4. Active autoimmune disease.

5. Subjects can not have an active immunodeficiency disorder, e.g. HIV

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety

Outcome Time Frame:

5 years

Safety Issue:

Yes

Principal Investigator

Mary L Disis, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Washington

Authority:

United States: Food and Drug Administration

Study ID:

6304

NCT ID:

NCT00194714

Start Date:

June 2004

Completion Date:

Related Keywords:

  • Breast Cancer
  • Breast cancer
  • Stage IV
  • HER2/neu+
  • Breast Neoplasms

Name

Location

University of Washington Seattle, Washington  98195