Vaccine Therapy in Treating Patients With Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells that express HER2/neu. Biological therapies, such as GM-CSF, may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether vaccine therapy is more effective than GM-CSF in treating breast cancer. PURPOSE: This randomized phase II trial is studying vaccine therapy to see how well it works compared with GM-CSF in treating patients with breast cancer.

Detailed Description
-----------------
OBJECTIVES: To determine if the GP2 peptide/GM-CSF vaccine reduces the recurrence rate in HLA-A2-positive, HER2/neu-positive, node-positive, or high-risk node-negative breast cancer patients randomized to receive the vaccine versus the immunoadjuvant, sargramostim (GM-CSF), alone. To determine if the AE37 peptide/GM-CSF vaccine reduces the recurrence rate in HLA-A2-negative, HER2/neu-positive, node-positive or high-risk node-negative breast cancer patients randomized to receive the vaccine versus the immunoadjuvant, GM-CSF, alone. To monitor the invitro and invivo immunologic responses to the vaccines and correlate these responses with the clinical outcomes. To monitor for any unexpected toxicities with the vaccines. OUTLINE: This is a multicenter study. Patients are stratified according to nodal status. Patients are randomized to 1 of 4 treatment arms. Arm I: HLA-A2-positive patients receive GP2 peptide/GM-CSF vaccine intradermally (ID) every 3-4 weeks for a total of up to 6 inoculations. Arm II: HLA-A2-positive patients receive solely GM-CSF ID Arm III: HLA-A2-negative patients receive AE37 peptide/GM-CSF vaccine ID every 3-4 weeks for a total of up to 6 inoculations. Arm IV: HLA-A2-negative patients receive solely GM-CSF ID After completion of study therapy, patients are followed every 3 months for the first 24 months and then every 6 months for an additional 36 months. Booster inoculations are administered at 12, 18, 24, and 30 months from the date of patients' enrollment into the study. One booster inoculation is administered at each timepoint (+/- 2 weeks) and will be the same inoculation (vaccine or GM-CSF only) as what patients received during their regular inoculation series.

Official Title
-----------------
Phase II Trial of the HER2/Neu Peptide GP2 + GM-CSF Vaccine vs GM-CSF Alone in HLA-A2+ OR the Modified HER2/Neu Peptide AE37 + GM-CSF Vaccine vs GM-CSF Alone in HLA-A2- Node-Positive and High-Risk Node-Negative Breast Cancer Patients

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Biological: GP2 peptide + GM-CSF vaccine
* Biological: GM-CSF (sargramostim)
* Biological: AE37 + GM-CSF vaccine
* Biological: GM-CSF (sargramostim)


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Inclusion criteria: Lymph node-positive breast cancer or high-risk lymph node-negative breast cancer. The latter is defined by any one of the following criteria: T2 disease Grade 3 disease Lymphovascular invasion Estrogen receptor- or progesterone receptor-negative disease HER2/neu-expressing tumor (immunohistochemistry [IHC] 3+ and/or amplified fluorescence in situ hybridization [FISH] >2.2, or N0 (i+)) HER2/neu-expressing tumor (IHC 1-3+ and or positive FISH >1.2) Completion of primary standard of care breast cancer therapies (i.e., surgery, chemotherapy, immunotherapy and radiation therapy as appropriate per standard of care for patients' specific cancer) Clinically cancer-free (no evidence of disease) Patients may be enrolled between 1-6 months from completion of standard primary breast cancer therapies Good performance status (as defined in Exclusion Criteria) Capable of informed consent Exclusion criteria: HER2/neu-negative breast cancers (IHC 0) Clinical and/or radiographic evidence of residual or persistent breast cancer Receiving immunosuppressive therapy to include chemotherapy, steroids, or methotrexate In poor health (Karnofsky <60%, ECOG >/-2) Total bilirubin >1.8, creatinine >2, hemoglobin <10, platelets <50,000, WBC <2,000) Active interstitial lung disease; asthma requiring more than as needed bronchodilators for management; or other autoimmune lung disease Pregnancy (urine hCG) Breast feeding History of autoimmune disease Involved in other experimental protocols (except with permission of the other study PI) PATIENT CHARACTERISTICS: Inclusion criteria: Female or male Menopausal status not specified Immunologically intact by recall anergy testing Negative pregnancy test Exclusion criteria: Karnofsky 0-60% or ECOG ≥ 2 Total bilirubin > 1.8 g/dL Creatinine > 2.0 g/dL Hemoglobin < 10.0 g/dL Platelet count < 50,000/mm³ WBC< 2,000/mm³ Active pulmonary disease requiring medication that includes multiple inhalers Pregnancy Breastfeeding History of autoimmune disease PRIOR CONCURRENT THERAPY: Inclusion criteria: See Disease Characteristics Exclusion criteria: Concurrent immunosuppressive therapy including chemotherapy, steroids, or methotrexate Concurrent participation in another experimental treatment (except with permission of the other study investigator)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>HLA-A2-positive patients receive GP2 peptide + GM-CSF vaccine intradermally (ID) every 3-4 weeks for a total of up to 6 inoculations. | Biological: GP2 peptide + GM-CSF vaccine<br>* Given intradermally every 3-4 weeks for a total of up to 6 inoculations<br>* Other names: GM-CSF (sargramostim);|
| Active Comparator: Arm II<br>HLA-A2-positive patients receive GM-CSF ID every 3-4 weeks for a total of up to 6 inoculations. | Biological: GM-CSF (sargramostim)<br>* GM-CSF given intradermally very 3-4 weeks for a total of up to 6 inoculations<br>|
| Experimental: Arm III<br>HLA-A2-negative patients receive AE37 peptide/GM-CSF vaccine ID every 3-4 weeks for a total of up to 6 inoculations. | Biological: AE37 + GM-CSF vaccine<br>* Given intradermally every 3-4 weeks for a total of up to 6 inoculations<br>* Other names: GM-CSF (sargramostim);|
| Active Comparator: Arm IV<br>HLA-A2-negative patients receive GM-CSF ID ID every 3-4 weeks for a total of up to 6 inoculations | Biological: GM-CSF (sargramostim)<br>* Given intradermally every 3-4 weeks for a total of up to 6 inoculations<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease recurrence | The following will be compared: disease recurrence rates between HLA-A2-negative patients receiving the AE37 + GM-CSF vaccine and HLA-A2-negative patients receiving GM-CSF alone disease recurrence rates between HLA-A2-positive patients receiving the GP2 + GM-CSF vaccine and HLA-A2-positive patients receiving GM-CSF alone disease recurrence rates between all four arms of the trial. | Five years (from date of enrollment to the study through the end of the follow-up period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Inoculations will be immediately halted if any serious adverse reactions occur which, when based upon appropriate judgment of the PI, are determined to jeopardize the patient or require medical or surgical intervention. Any death or grade 4 adverse drug experience found to be directly related to the experimental vaccine will result in suspension of patient enrollment to the study. | Local and systemic reactions to each inoculation will be monitored every six months during the regular inoculation series and the booster series. | 
| Immune Response | Immune response will be measured by proliferation assays, dimer assays, and ELISPOT. Delayed type hypersensitivity reactions will be compared between the vaccinated group and GM-CSF-only group. | Immune response will be measured after every monthly inoculation in the regular inoculation series and after each inoculation in the booster series | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, male breast cancer