Vaccine Therapy With or Without Polysaccharide-K in Patients With Stage IV HER2 Positive Breast Cancer Receiving HER2-Targeted Monoclonal Antibody Therapy

Study Overview
=================
Brief Summary
-----------------
This randomized phase I/II trial studies the side effects of vaccine therapy with or without polysaccharide-K and to see how well it works in treating patients with stage IV human epidermal growth factor receptor 2 (HER2) positive breast cancer who are receiving HER2-targeted monoclonal antibody therapy. Vaccines made from HER2 intracellular domain (ICD) peptide may help the body build an effective immune response to kill tumor cells that express HER2. Polysaccharide-K may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether vaccine therapy works better when given with or without polysaccharide-K in treating breast cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the safety of polysaccharide-K (PSK) when given with HER2-directed immunotherapy. SECONDARY OBJECTIVES: I. To evaluate the effect of PSK on natural killer (NK) cell functional activity when given with HER2-directed immunotherapy. TERTIARY OBJECTIVES: I. To investigate the effect of PSK when given with HER2-directed immunotherapy on: serum levels of pro-inflammatory cytokine and/or chemokines; intermolecular epitope spreading; serum transforming growth factor (TGF)-beta levels; progression free survival (PFS) and overall survival (OS). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive HER2 ICD peptide-based vaccine intradermally (ID) once monthly for 3 months, trastuzumab (or trastuzumab and pertuzumab) per standard of care, and placebo orally (PO) twice daily (BID) for 4 months. ARM II: Patients receive HER2 ICD peptide-based vaccine ID and trastuzumab (or trastuzumab and pertuzumab) as in Arm I and polysaccharide-K PO BID for 4 months. After completion of study treatment, patients are followed up for 9 months and then twice annually for 3 years.

Official Title
-----------------
Phase I/II Randomized Study of Combination Immunotherapy With or Without Polysaccharide Krestin (PSK®) Concurrently With a HER2 ICD Peptide-Based Vaccine in Patients With Stage IV Breast Cancer Receiving HER2-Targeted Monoclonal Antibody Therapy

Conditions
-----------------
HER2/Neu Positive, Recurrent Breast Carcinoma, Stage IV Breast Cancer

Intervention / Treatment
-----------------
* Biological: HER-2/neu Intracellular Domain Protein
* Other: Laboratory Biomarker Analysis
* Biological: Pertuzumab
* Other: Placebo
* Biological: Polysaccharide-K
* Biological: Trastuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with stage IV HER2+ breast cancer treated to: No evidence of disease (NED), or Stable bone only disease after definitive therapy HER2 overexpression by immunohistochemistry (IHC) of 2+ or 3+ in the primary tumor or metastasis; or documented gene amplification by fluorescent in situ hybridization (FISH) analysis; IHC =< 2+ must have HER2 gene amplification documented by FISH Patients must continue HER2-targeted monoclonal antibody therapy dosing per standard of care through the entire study period (one year) HER2-targeted monoclonal antibody therapy is defined as either trastuzumab monotherapy, or trastuzumab and pertuzumab combination therapy administered per standard of care Patients must be at least 21 days post cytotoxic chemotherapy prior to enrollment Patients must be at least 28 days post immunosuppressants prior to enrollment Patients must be at least 28 days from use of any mushroom supplements (examples: turkey tail, reishi, maitake, shiitake) and agree to withhold them for the entire study period (one year) Patients on bisphosphonates and/or endocrine therapy are eligible Patients who are having sex that could lead to pregnancy must agree to contraceptive use during the entire study period Patients must have Zubrod performance status score of =< 2 Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have significant active concurrent medical illnesses precluding study treatment White blood cell (WBC) >= 3000/mm^3 Hemoglobin (Hgb) >= 10 g/dl Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 1.5 mg/dl Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 times the upper limit of normal Patients must have adequate cardiac function as demonstrated by normal left ventricular ejection fraction (LVEF) >= the lower limit of normal for the facility on multi gated acquisition (MUGA) scan or echocardiogram (ECHO) within 3 months of enrollment Exclusion Criteria: Patients with any of the following cardiac conditions: Restrictive cardiomyopathy Unstable angina within 6 months prior to enrollment New York Heart Association functional class III-IV heart failure Symptomatic pericardial effusion Patients with any contraindication to receiving rhu granulocyte macrophage colony stimulating factor (rhuGM-CSF) based products Patients with any clinically significant autoimmune disease requiring active treatment Patients receiving any concurrent immunosuppressants Patients who are pregnant or breast-feeding Patients who are simultaneously enrolled in other treatment studies Patients who have received a previous HER2 breast cancer vaccine Known hypersensitivity reaction to mushroom products

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

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (placebo)<br>Patients receive HER2 ICD peptide-based vaccine ID once monthly for 3 months, trastuzumab (or trastuzumab and pertuzumab) per standard of care, and placebo PO BID for 4 months. | Biological: HER-2/neu Intracellular Domain Protein<br>* Given ID<br>* Other names: HER2 Intracellular Domain;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pertuzumab<br>* Given per standard of care<br>* Other names: RO4368451;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Biological: Trastuzumab<br>* Given per standard of care<br>* Other names: Trastuzumab Biosimilar PF-05280014;|
| Experimental: Arm II (polysaccharide-K)<br>Patients receive HER2 ICD peptide-based vaccine ID and trastuzumab (or trastuzumab and pertuzumab) as in Arm I and polysaccharide-K PO BID for 4 months. | Biological: HER-2/neu Intracellular Domain Protein<br>* Given ID<br>* Other names: HER2 Intracellular Domain;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pertuzumab<br>* Given per standard of care<br>* Other names: RO4368451;Biological: Polysaccharide-K<br>* Given PO<br>* Other names: PSK;Biological: Trastuzumab<br>* Given per standard of care<br>* Other names: Trastuzumab Biosimilar PF-05280014;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 or Higher Toxicity Per Study Arm. | Evaluated using physical examinations and clinical labs by type and grade of toxicities noted during treatment, There were graded per Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events 4.0. | Up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction of Interferon (IFN)-Gamma Production and Cluster of Differentiation (CD)107a Expression in NK Cells, Via Flow Cytometry | Augmentation of NK cell activity is defined by a 2-fold increase (at time of maximal change) in NK cell IFN-gamma production and CD107a expression For the results we used CD56 which is the accepted phenotypic marker for natural killer (NK) cells and CD16 which is a receptor on NK cells that facilitates antibody-dependent cellular cytotoxicity (ADCC). CD56dim are typically responsible for cytolytic activity and targets cell killing, whereas, CD56bright are the main source of cytokine production (i.e. IFN-gamma). CD56dim CD16bright NK cells represent at least 90% of all peripheral blood NK cells with a maximum of 10% as CD56bright NK cells We compared the baseline expression of CD56brightCD16dim or CD56dimCD16bright (prior to start of study treatment) to the maximum expression of CD56brightCD16dim or CD56dimCD16bright at 1 of 4 timepoints after the start of the oral administration of study treatment (polysaccharide-K/placebo (either week 4, 8, 12 or 16). | Up to 16 weeks |