Efficacy and Safety Study of NeuVax™ (Nelipepimut-S or E75) Vaccine to Prevent Breast Cancer Recurrence

Purpose of this trial:

1. To assess the efficacy and safety of NeuVax™ administered with adjuvant Leukine® (sargramostim, GM-CSF).
2. To evaluate and compare the disease free survival (DFS) in the vaccinated and control subjects.

This is a multicenter, multinational, prospective, randomized, double-blind, controlled Phase 3 study.

The subjects eligible for this trial have an early stage node-positive breast cancer. Their tumors express low or intermediate levels of the HER2 protein. NeuVax™ will be administered after completion of front-line, standard of care therapy (surgery, radiation therapy, and chemotherapy) and can be given concomitantly with physician prescribed endocrine treatment.

NeuVax™ is the immmunodominant nonapeptide derived from the extracellular domain of the HER2 protein, a well-established target for therapeutic intervention in breast carcinoma. The nelipepimut sequence stimulates specific CD8+ cytotoxic T lymphocytes (CTL) following binding to HLA-A2/A3 molecules on antigen presenting cells (APC). These activated specific CTLs recognize, neutralize and destroy through cell lysis HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci. The nelipepimut immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading. Based on a successful Phase 2 trial, which achieved its primary endpoint of DFS, the Food and Drug Administration (FDA) granted NeuVax a Special Protocol Assessment (SPA) for its Phase 3 PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment) study.

The active portion of the study will last three years (36 months). The follow-up will last from 5 to 10 years.

Endpoints:

1. Primary efficacy endpoint:

   * 3-year DFS
2. Secondary efficacy endpoints:

   * 5- and 10-year DFS
   * 3-year OS
   * 5- and 10-year OS
   * Safety profile, and adverse events (AEs)
   * Patterns of recurrence to include Time to recurrence (TTR), time to local recurrence (TTLR), time to distant recurrence (TTDR), time to bone metastases (TTBM)

Safety Assessments:

Subjects will be assessed at every study visit for the safety endpoints, AEs,vital signs, physical examinations and laboratory data; yearly follow-up of survival will include imaging studies, ECGs, MUGA or ECHO scans and concomitant medications.

Eligibility Criteria:
Key Inclusion Criteria:

* Pathological diagnosis of invasive adenocarcinoma of the breast
* Breast cancer completely excised, or patient receiving neoadjuvant therapy prior to surgery
* One of these 2 surgical treatments and axillary staging with sentinel lymph node dissection or axillary dissection level I/II:

  1. Total mastectomy-patients with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II
  2. BCS (lumpectomy)-patients 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
* Node-positive disease
* Primary tumor stage T1-3 at initial diagnosis
* HER2 negative (HER2 1+ by IHC or HER2 2+ by IHC/FISH)
* HLA-A2 or HLA-A3 haplotype
* Completed NCCN approved neo-adjuvant/adjuvant chemotherapy or both
* Completed radiation therapy
* No evidence of disease
* Able and willing (or have legal representative) to understand the study and provide consent

Key Exclusion Criteria:

* Bilateral breast malignancy or suspicious mass in opposite breast
* Inflammatory breast malignancy
* History of prior breast cancer, ductal carcinoma in situ
* Prior trastuzumab therapy
* New York Heart Association Stage 3 or 4 cardiac disease
* Sensory/motor neuropathy ≥ Grade 2
* Autoimmune diseases or immune deficiency disease
* Subjects on chronic steroid therapy, other immunosuppressive therapy