PRESENT: Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax[?] Treatment

Summary

The primary efficacy endpoint is DFS and the secondary efficacy endpoints are 3-year oS, 5- and 10-year DFS and oS, time recurrence, and safety. Four formal analyses are planned. The first will occur upon reaching 50% (n[?]70) of the required DFS events.This analysis will be used for assessing efficacy (DFS), futility, and an overall safety evaluation.The second will occur upon reaching 100% (n[?]139) of the required DFS events, or after 36
months of follow-up following enrollment of the last subject, whichever is greater. This analysis will be used for assessing oS futility and an overall safety evaluation. The third analysis will occur upon reaching 100% (n[?]139) of the required oS events, or after 60 months of follow-up following enrollment of the last subject, whichever is greater. The fourth and final analysis will occur after 120 months of follow-up following enrollment of the last subject.

Two informed consent documents will be used in the recruitment of subjects into the trial. The first is to obtain permission for screening, haplotyping, determination of tissue availability for HeR2 reanalysis, and evaluation of eligibility procedures. Subjects who meet the HLa-a2, HLa-a3, and HeR2 inclusion criteria will go on to sign the second informed consent for randomization and treatment. Randomization and initiation of study vaccinations will occur at no more than 12 weeks (and no sooner than 1 month) from completion of last standard of care adjuvant chemotherapy or radiotherapy, or both and at no evidence of disease (neD). Furthermore, eR/PR and HeR2 data are to be reconfirmed before subject randomization. Subjects will first be stratified by stage (iia, iiB, or iiia); type of surgery (mastectomy vs breast conserving surgery [BCS]), hormone receptor status (with either eR+ or PR+ vs both eR- and
PR-) menopausal status (pre- or perimenopausal vs postmenopausal). an interactive voice response system (iVRS) will be used to randomly assign subjects to the 2 treatment groups in a 1:1 allocation using an institution balancing algorithm with a fixed key size. once stratified, eligible subjects will be randomized to receive rhGM-CSF only or neuVax[TM] .

Both groups will receive standard of care follow-up surveillance including: interval history and physical examination every 6 months for 5 years, then annually; clinical breast examination every 12 months; annual mammogram (and at 12 months post-radiation therapy if breast conserved). in addition, study required follow-up surveillance will include yearly assessment of the following:

* Complete blood count (CBC) with differential and platelet count
* Serum chemistry (creatinine, Bun, bili, aLT, aST, LDH, alk Phos)
* Pregnancy test, during the treatment period
* electrocardiogram (eCG), yearly through Year 3, and then as ordered by the treating physician
* Bone scan or PeT, yearly through Year 3, and then at Years 5 and 10
* Computed tomography (CT) (chest, abdomen and pelvis) or magnetic resonance imaging (MRi), yearly through Year 3, and then at Years 5 and 10
* MuGa scan or eCHo will be conducted at baseline, at 3 and 6 months and at 6 month intervals for 3 years, and yearly thereafter for up to 10 years for subjects who show changes in LVeF or express signs or symptoms or if radiographic evidence of cardiac dysfunction is observed.

This is designed as a double-blinded study. Treatment will be masked to the subject and the investigator. The inoculations will be administered monthly for 6 doses, then every 6 months for 5 doses for a total of 11 doses given over a period of 36 months. Subjects will be followed thereafter for up to 10 years.

Participant Eligibility

1. Women, at least 18 years of age.
2. Pathological diagnosis of invasive adenocarcinoma of the breast.
3. Breast cancer completely excised, or patient receiving neoadjuvant therapy prior to surgery.
4. One of these 2 surgical treatments

* Total mastectomy and axillary staging with sentinel lymph node dissection or axillary dissection level I/II. Patients with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II.

* BCS (lumpectomy) and axillary staging with sentinel lymph node dissection or axillary dissection level I/II. 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.
5. Node-positive disease defined as:

* Clinically node positive disease in patients who present with a suspicious lymph node on physical examination or identified by radiologic imaging that is confirmed histologically by core biopsy or cytologically by fine needle aspiration biopsy. These patients will qualify even if final pathological assessment of their lymph nodes is negative (pN0) following neoadjuvant chemotherapy.

* Pathologic pN1 (including pN1mi) or pN2 disease for patients undergoing surgery as initial intervention.
6. Primary tumor stage T1-3 at time of initial breast cancer diagnosis. Ipsilateral nodes must be N0-1 by clinical evaluation and pN1 M0 or pN2 M0 (Appendix 3).
7. HER2 Tumor tissue status - is to be confirmed in a Central Laboratory using IHC test (Bond(TM) Oracle(TM) HER2 IHC System III, Leica Biosystems) or the same FISH test (PathVysion(TM) HER2 DNA Probe Kit, Abbott Diagnostics) as follows:

* HER2 expression levels as 1+ or 2+ will be determined by IHC via Bond(TM) Oracle(TM) HER2 IHC System III, Leica Biosystems)

* HER2 IHC 2+ intensity gene amplification will be confirmed by Abbott FISH PathVysion HER2 DNA Probe Kit determining the HER2 gene count and HER2 gene/ CEP17 ratio of 2. 0 or less (according to FISH PathVysion Package Insert).

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Update Note to File:
Patients who are potentially eligible for the PRESENT trial, if HER2 negative by local IHC, FISH negative or who have not been screened in a local lab for IHC, should be screened in the central
lab. If the patient is IHC 1+ or 2+, they will be included in the study, assuming they meet all other
inclusion/exclusion criteria.

During the call with FDA yesterday, (4June2013) we requested, and were authorized, to start screening those patients who were determined as HER2 0 by the local labs at their initial diagnosis,
immediately, i.e., prior to protocol approval.
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8. Hormone receptor (ER/PR) status determined by qualified laboratory.
9. Must complete approved regimen of neoadjuvant or adjuvant chemotherapy, or both, consisting of at least 4 cycles (described in detail in Appendix 1) before receiving study treatment (and subjects must have recovered (toxicity recovered to <= Grade 1) from effect of recent surgery, radiotherapy, or adjuvant chemotherapy as determined by the principal investigator).
10. Must be no more than 12 weeks and no sooner than 1 month from completion of last standard of care therapy, (surgery, adjuvant chemo- or radiotherapy), at the time of first study treatment and with no evidence of disease (NED).
11. Must complete approved radiation therapy for subjects with total mastectomy prior to receiving study treatment:

* 1-3 positive axillary nodes x chest wall irradiation and irradiation to the infraclavicular and supraclavicular areas and to the internal mammary nodes is not mandatory but may be administered at the discretion of the treating radiation oncologist.

* >= 4 <10 positive axillary nodes x chest wall irradiation and irradiation to the infraclavicular and supraclavicular area are mandatory; Irradiation to the axillaryarea is not mandatory; irradiation of the internal mammary nodes is not mandatory.
12. Must complete approved radiation therapy for subjects with BCS prior to receiving study treatment: Adjuvant breast radiation is indicated for all subjects treated with breast conservation (whole breast irradiation with or without
* boost
* dose of radiation to the
tumor bed):1 to 3 positive axillary nodes: irradiation to the supraclavicular area is not mandatory;
irradiation to the axillary area is not mandatory; irradiation of the internal mammary
nodes is not mandatory.

* >= 4 <10 positive axillary: irradiation to the infraclavicular and supraclavicular areas is
mandatory; irradiation to the axillary area is not mandatory irradiation of the
internal mammary nodes is not mandatory.
13. Subjects with hormone-receptorxpositive disease must have adjuvant endocrine therapy
after chemotherapy (unless contraindicated).
14. All subjects[Single Quote] willingness for partner use of condom while on study treatment and for 90 days after the last dose of study drug. Additionally, if able to conceive, must agree to double barrier birth control, (i.e.: spermicidal foam, gel, etc.) in addition to partner use of condom
15. Subject or legal representative is able to understand the study objectives and procedures
and is willing to show consent by signing the informed consent documents.

4.2.3 Inclusion Criteria for Randomization (Second Qualification Visit)
1. Met all inclusion criteria for HLA typing.
2. HLA-A2 or HLA-A3 haplotype as determined by a third party central lab.
3. Normal CBC with differential (see Table 8: Hematology and Clinical Laboratory
Ranges for Eligibility).
4. Clinical chemistry less than 2x normal upper limit of normal range (see Table 8: Hematology and Clinical Laboratory Ranges for Eligibility).
5. Adequate kidney and liver function as measured by creatinine, bilirubin, and liver enzymes (see Table 8: Hematology and Clinical Laboratory Ranges for Eligibility).
6. ECHO or MUGA scan with cardiac LVEF >50%, or within normal range for performing institution, and less than 10% decrease from baseline (post-adjuvant chemotherapy, if available).
7. HER2 expression status determined to be IHC 1+ or 2+ in a Central Laboratory with Bond(TM) Oracle(TM) HER2 IHC System-III (Leica Biosystems). If HER2 status is 2+, amplified, it is confirmed in qualified Central lab by Abbott FISH test, PathVysion(TM) HER2 DNA Probe Kit (ratio of 2. 0 or less).