This will be a multi-center, prospective, randomized, single-blinded, placebo-controlled phase II trial of trastuzumab + nelipepimut-S/GM-CSF versus trastuzumab + GM-CSF alone. Our target study population is high-risk HER2-positive breast cancer patients. High-risk HER2-positive breast cancer patients are defined as:

Those with HER2-positive breast cancer, regardless of hormone receptor status, who receive neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy, and fail to achieve a pCR.

Those with HER2-positive breast cancer, regardless of hormone receptor status, who undergo surgery as a first intervention and are found to have ≥ 4 positive lymph nodes.

Those with HER2-positive, hormone receptor negative breast cancer who undergo surgery as a first intervention and are found to have 1-3 positive lymph nodes.

Disease-free subjects after standard of care multi-modality therapy will be screened and HLA-typed.

In this study, the investigators intend to assess the ability of the combination of trastuzumab and the HER2 vaccine nelipepimut-S (administered with the immunoadjuvant GM-CSF) given in the adjuvant setting to prevent recurrences in patients with high-risk HER2-positive breast cancer. High-risk is defined as those patients that do not achieve a pCR after neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy or those who undergo upfront surgery and are found to have greater than or equal to four positive lymph nodes regardless of hormone receptor status or 1-3 positive lymph nodes and are hormone receptor negative.

Following surgery, patients will be screened and HLA-typed (consent #1). Nelipepimut-S is a CD8-eliciting peptide vaccine that is restricted to HLA-2+ or HLA-A3+ or HLA-A24+ or HLA-A26+ patients (approximately 80% of the US population). HLA-A2+/A3+/A24+/orA26+ patients who meet all other eligibility criteria will be randomized to receive trastuzumab + nelipepimut-S/GM-CSF or trastuzumab + GM-CSF alone (consent #2). The trastuzumab will be administered to all patients consistent with current standard of care. Patients randomized to the nelipepimut-S/GM-CSF arm will receive vaccinations of nelipepimut-S (1000 mcg) and GM-CSF (250 mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series. Patients randomized to the GM-CSF alone arm will receive inoculations of GM-CSF (250 mcg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF. Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone.

Upon completion of the primary vaccination/inoculation series, booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 6 months ± 2 weeks after the completion of the PVS, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following time points after completion of the PVS: 6 months ± 2 weeks, 12 months ± 2 weeks, 18 months ± 2 weeks, 24 months ± 2 weeks. Booster inoculations will occur for patients randomized to receive nelipepimut-S/GM-CSF as well as patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs and dosing (i.e., nelipepimut-S/GM-CSF patients will be boosted with nelipepimut-S/GM-CSF while GM-CSF alone patients will be boosted with GM-CSF alone). Patient blinding will be maintained throughout the study.

Subjects will be followed for safety issues, immunologic response and clinical recurrence. Patients will be monitored 48-72 hours after each inoculation for reaction to the inoculation as well as documentation of any adverse effects experienced. Immunologic response will be monitored primarily by in vivo delayed type hypersensitivity (DTH) reactions but also may be documented by other immunologic assays. All patients will be followed for a total of 36 months from the time of initiation of trastuzumab maintenance therapy to document disease-free status.

Inclusion criteria:

• 18 years or older

• Eastern Cooperative Oncology Group (ECOG) performance status 0,1

• AJCC stage I - III non-inflammatory, HER2-positive (according to ASCO-CAP guidelines 5) breast cancer

• Completed neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy and underwent surgery with final pathology showing evidence of residual disease in the breast or axilla (residual ductal carcinoma in situ or microinvasive disease not eligible) or underwent surgery as a first intervention and was found to be pathologically node-positive: ≥ 4 positive lymph nodes (pN2 or pN3) regardless of hormone receptor status or 1-3 positive lymph nodes (pN1) if hormone receptor negative. Patients with micrometastases (pN1mi) are not eligible.

• Completed an approved regimen of neoadjuvant or adjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy with plan for completion of one year of trastuzumab therapy.

• Completed appropriate surgical therapy to include:

  1. Total mastectomy and axillary staging with sentinel lymph node dissection or axillary lymph node dissection (level I/II). Patients with a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
  2. Breast conserving surgery (BCS) and axillary staging with sentinel lymph node dissection or axillary lymph node dissection. Patients undergoing surgery as a first intervention with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II unless they had clinically node negative T1-T2 tumors and fewer than 3 involved lymph nodes. Patients receiving neoadjuvant chemotherapy that have a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
  3. Completed or receiving appropriate radiation therapy if indicated:

For patients undergoing total mastectomy surgery as a first intervention, post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

• For patients undergoing breast conserving surgery (BCS) as a first intervention, whole breast irradiation with or without a boost, and radiation to the infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, whole breast irradiation with or without a boost is required. Radiation to the infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating medical oncologist.

• For patient's undergoing mastectomy after neoadjuvant chemotherapy post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients presenting with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

• For patient's undergoing BCS after neoadjuvant chemotherapy, whole breast irradiation with or without a boost is required. For patients with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery, radiation to the infraclavicular and supraclavicular areas is required. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, radiation to the infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

  • HLA-A2+ or HLA-A3+ or HLA-A24+ or HLA-A26+

  • LVEF >50%, or an LVEF within the normal limits of the institution's specific testing (MUGA or ECHO)

  • Adequate organ function as determined by the following laboratory values:

    1. ANC ≥ 1,000/μL
    2. Platelets ≥ 75,000/μL
    3. Hgb ≥ 9 g/dL
    4. Creatinine ≤ 1.5 x upper limit of normal (ULN) of institution's range or Creatinine clearance ≥ 50%
    5. Total bilirubin ≤ 1.5 ULN of institution's range
    6. ALT and AST ≤ 1.5 ULN of institution's range
    7. For women of child-bearing potential, agreement to use adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms)

  • Signed informed consent

Exclusion criteria:

• AJCC Stage IV breast cancer
• NYHA stage 3 or 4 congestive heart failure
• Immune deficiency disease or known history of HIV, HBV, HCV
• Receiving immunosuppressive therapy including chronic steroids, methotrexate, or other known immunosuppressive agents
• Pregnancy (assessed by urine HCG)
• Breast feeding
• Any active autoimmune disease requiring treatment, with the exception of vitiligo
• Active pulmonary disease requiring medication to include multiple inhalers (>3 inhalers including one containing steroids)
• Involved in other experimental protocols except with permission of other PI