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

Study Overview
=================
Brief Summary
-----------------
Purpose of this trial: To assess the efficacy and safety of NeuVax™ administered with adjuvant Leukine® (sargramostim, GM-CSF). To evaluate and compare the disease free survival (DFS) in the vaccinated and control subjects.

Detailed Description
-----------------
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: Primary efficacy endpoint: 3-year DFS 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.

Official Title
-----------------
PRESENT: Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer With Low to Intermediate HER2 Expressions With NeuVax™Treatment

Conditions
-----------------
Breast Cancer With Low to Intermediate HER2 Expression

Intervention / Treatment
-----------------
* Biological: NeuVax™ vaccine
* Biological: Leukine® (sargramostim, GM-CSF) and water for injection


Participation Criteria
=================
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: Total mastectomy-patients with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II 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

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NeuVax™<br>NeuVax™ in WFI solution with Leukine® | Biological: NeuVax™ vaccine<br>* E75 peptide acetate (HER2/neu p366-379) in WFI (1.5 mg/mL) mixed with 250 micrograms Leukine® (sargramostim, GM-CSF), will be administered in intradermal injections, in four divided doses (4 sites on upper thigh) once a month, for six consecutive months. At the end of the six months, NeuVax™ vaccine boosters will be given the same way once every six months for the next five times (totaling 36 months).<br>* Other names: E75 peptide acetate , WFI, sargramostim, GM-CSF;|
| Active Comparator: Leukine®<br>Leukine® with WFI | Biological: Leukine® (sargramostim, GM-CSF) and water for injection<br>* Leukine® 250 micrograms in water for injection, will be administered in intradermal injections, in four divided doses (4 sites on upper thigh) once a month, for six consecutive months. At the end of the six months, boosters inoculations will be given the same way once every six months for the next five times (totaling 36 months).<br>* Other names: Leukine®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of DFS in vaccine treated patients and control patients | The primary objective is to compare the DFS in subjects with operable early-stage, node-positive breast cancer who receive standard of care multimodality therapy plus NeuVax™ as the treatment group or standard of care multimodality therapy plus the vaccine adjuvant, Leukine® as the control group. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of DFS and OS at 3, 5 and 10 years in vaccine and control groups, respectively; assessment of safety | The secondary objectives are to evaluate the 2 groups of subjects for: 5- and 10-year DFS 3-year OS 5- and 10-year OS Time to recurrence (TTR), time to local recurrence (TTLR), time to distant recurrence (TTDR), time to bone metastases (TTBM) Overall safety profile and adverse events (AEs) | 3 through 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HER2, low or intermediate, breast cancer, node-positive tumors