TPIV100 and Sargramostim for the Treatment of HER2 Positive, Stage II-III Breast Cancer in Patients With Residual Disease After Chemotherapy and Surgery

Inclusion Criteria:

• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Histologically confirmedadenocarcinoma of the breast stage >= T2 OR >= N1 based on the 7th edition of tumor,node, metastases (TNM) staging system from the American Joint Committee on Cancer
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any estrogen receptor (ER)or progesterone receptor (PR) but HER2 positive defined as 3+ staining intensity (on ascale of 0 to 3) by means of immunohistochemistry (IHC) analysis OR gene amplificationon fluorescence in situ hybridization (FISH) ratio >= 2.0
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willingness to provideadequate pretreatment biopsy sample
• NOTE: Adequate tissue samples defined as core needle biopsy or incisional biopsyor excisional samples that can provide >= 3 core needle biopsies with at least 14gauge (G) needle with 12 unstained sections of 5 micron thickness. Fine needleaspiration (FNA) sample alone is not sufficient
• NOTE: Patients without adequate pretreatment biopsy samples must be agreeable tohave an additional research biopsy prior to neoadjuvant therapy
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Eastern CooperativeOncology Group (ECOG) performance status (PS) 0, 1, 2
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to employ adequatecontraception from the time of pre-registration through 6 months after the finalvaccine cycle
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to receive atetanus vaccination if subject has not had one =< 1 year prior to pre-registration
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Provide written informedconsent
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to return toenrolling institution for follow-up (during the Active Monitoring Phase of the study)
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to providemandatory tissue and blood samples for correlative research purposes
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Negative pregnancy testdone =< 7 days prior to pre-registration, for persons of childbearing potential only
• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required
• REGISTRATION (SAFETY LEAD-IN): Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to registration)
• REGISTRATION (SAFETY LEAD-IN): Platelet count >= 75,000/mm^3 (obtained =< 28 daysprior to registration)
• REGISTRATION (SAFETY LEAD-IN): Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior toregistration)
• REGISTRATION (SAFETY LEAD-IN): Direct bilirubin < 1.5 x upper limit of normal (ULN) (obtained =< 28 days prior to registration)
• REGISTRATION (SAFETY LEAD-IN): Aspartate transaminase (AST) =< 3 x ULN (obtained =< 28days prior to registration)
• REGISTRATION (SAFETY LEAD-IN): Creatinine =< 2 x ULN (obtained =< 28 days prior toregistration)
• REGISTRATION (SAFETY LEAD-IN): Prothrombin time (PT)/international normalized ratio (INR)/ partial thromboplastin time (PTT) =< 1.5 x ULN OR if patient is receivinganticoagulant therapy and PT or PTT is within therapeutic range of intended use ofcoagulant (obtained =< 28 days prior to registration)
• REGISTRATION (SAFETY LEAD-IN): Completed planned curative breast surgeries (notincluding any future breast reconstructive surgery) and any radiation therapy >= 30days prior to registration
• REGISTRATION (SAFETY LEAD-IN): Completed last cycle of chemotherapy >= 90 days priorto registration
• NOTE: Prior to registration, patients must not receive > 8 cycles of TDM-1maintenance therapy after surgery
• REGISTRATION (SAFETY LEAD-IN): Any residual disease after trastuzumab +/- pertuzumabbased neoadjuvant chemotherapy warranted T-DM1 as per treating physician
• REGISTRATION (SAFETY LEAD-IN): Adequate tissue specimens from both pre-treatmentbiopsy and surgery must be submitted. Adequate tissue samples defined as core needlebiopsy or incisional biopsy or excisional samples that can provide >= 3 core needlebiopsies with at least 14G needle with 12 unstained sections of 5 micron thickness
• NOTE: Fine needle aspiration (FNA) sample alone is not sufficient
• REGISTRATION (SAFETY LEAD-IN): Negative pregnancy test done =< 7 days prior toregistration, for persons of childbearing potential only
• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required
• REGISTRATION (SAFETY LEAD-IN): ECOG performance status (PS) 0, 1, 2
• REGISTRATION (SAFETY LEAD-IN): Willing to employ adequate contraception from the timeof registration through 6 months after the final vaccine cycle
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): ECOGperformance status (PS) 0, 1, 2
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Absoluteneutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to registration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Plateletcount >= 75,000/mm^3 (obtained =< 28 days prior to registration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior to registration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Directbilirubin < 1.5 x upper limit of normal (ULN) (obtained =< 28 days prior toregistration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Aspartatetransaminase (AST) =< 3 x ULN (obtained =< 28 days prior to registration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Calculatedserum creatinine clearance of >= 50 mL/minute (min.) (obtained =< 28 days prior toregistration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): PT/INR/PTT =< 1.5 x ULN OR if patient is receiving anticoagulant therapy and PT or PTT is withintherapeutic range of intended use of coagulants (obtained =< 28 days prior toregistration)
• REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Negativepregnancy test done =< 7 days prior to registration, for person of childbearingpotential
• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Platelet count >= 75,000/mm^3 (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Direct bilirubin < 1.5 x upperlimit of normal (ULN) (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Aspartate transaminase (AST) =< 3x ULN (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Creatinine =< 2 x ULN (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): PT/INR/PTT =< 1.5 x ULN OR ifpatient is receiving anticoagulant therapy and PT or PTT is within therapeutic rangeof intended use of coagulant (obtained =< 28 days prior to randomization)
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Completed last cycle ofchemotherapy >= 90 days prior to randomization
• NOTE: Prior to randomization, patients must not receive >= 6 cycles of T-DM1maintenance therapy after surgery
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Have residual disease with >= 1cm residual tumor in the breast (>= ypT1c) and/or persistent lymph node positivityafter trastuzumab +/- pertuzumab based neoadjuvant chemotherapy
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Adequate tissue specimens fromboth pre-treatment biopsy and surgery must be submitted. Adequate tissue samplesdefined as core needle biopsy or incisional biopsy or excisional samples that canprovide >= 3 core needle biopsies with at least 14G needle with 12 unstained sectionsof 5 micron thickness
• NOTE: Fine needle aspiration (FNA) sample alone is not sufficient
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Negative pregnancy test done =< 7days prior to randomization, for persons of childbearing potential only
• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): ECOG performance status (PS) 0, 1, 2
• RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Willing to employ adequatecontraception from the time of randomization through 6 months after the final vaccinecycle

Exclusion Criteria:

• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any of the followingbecause this study involves an investigational agent whose genotoxic, mutagenic andteratogenic effects on the developing fetus and newborn are unknown:
• Pregnant person
• Nursing person unwilling to stop breast feeding
• Person of child bearing potential who are unwilling to employ adequatecontraception from the time of registration through 6 months after the finalvaccine cycle
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Clinical evidence ofactive local recurrence or distant metastases
• NOTE: All patients must have either a positron emission tomography (PET)/computedtomography (CT) or CT chest, abdomen, and pelvis with bone scan to rule outdistant metastases =< 365 days prior to preregistration. If any of these isconcerning, follow-up imaging or biopsy should be performed if indicated rule outdistant metastases
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Co-morbid systemicillnesses or other severe concurrent disease which, in the judgment of theinvestigator, would make the patient inappropriate for entry into this study orinterfere significantly with the proper assessment of safety and toxicity of theprescribed regimens
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Immunocompromised patientsincluding patients known to be human immunodeficiency virus (HIV) positive or those onchronic steroids
• NOTE: Must be off systemic steroids at least 14 days prior to pre-registration.However, topical steroids, inhalants or steroid eye drops are permitted
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Uncontrolled intercurrentillness including, but not limited to, ongoing or active infection, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatricillness/social situations that would limit compliance with study requirements
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Uncontrolled acute orchronic medical conditions including, but not limited to the following:
• Active infection requiring antibiotics
• Congestive heart failure with New York Heart Association class III or IV;moderate to severe objective evidence of cardiovascular disease
• Myocardial infarction or stroke =< 6 months prior to pre-registration
• Significant cardiac arrhythmia or unstable angina
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Receiving any otherinvestigational agent
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Other active malignancy attime of pre-registration or =< 3 years prior to preregistration
• EXCEPTIONS: Non-melanoma skin cancer or carcinoma-in-situ (e.g. of cervix,prostate)
• NOTE: If there is a history of prior malignancy, they must not be receiving otherspecific treatment (cytotoxics, monoclonal antibodies, small molecule inhibitors)for their cancer
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Known history of activeautoimmune disease that has required systemic treatment in the =< 30 days (i.e., withuse of disease modifying agents, corticosteroids, or immunosuppressive drugs) prior topre-registration. NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency) is notconsidered a form of systemic treatment. Patients with vitiligo, Graves disease, orpsoriasis not requiring systemic treatment within the past 30 days are not excluded.Patients with Celiac disease controlled with diet modification are not excluded
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any prior hypersensitivityor adverse reaction to granulocyte-macrophage colony stimulating factor (GM-CSF)
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): History oftrastuzumab-related cardiac toxicity requiring interruption or discontinuation oftherapy, even if left ventricular ejection fraction (LVEF) fully recovered
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Baseline LVEF < 50%
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Failure to fully recoverfrom acute, reversible effects of prior chemotherapy regardless of interval since lasttreatment
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): History of myocardialinfarction =< 168 days (6 months) prior to pre-registration, or congestive heartfailure requiring use of ongoing maintenance therapy for life threatening ventriculararrhythmias
• PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Patients who receivedtamoxifen or raloxifene or another agent for prevention of breast cancer =< 2 monthsprior to pre-registration