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

Phase 1

Completed

Conditions: Recurrent Breast Carcinoma
HER2/Neu Positive
Stage IV Breast Cancer

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

Registration Number: NCT01922921

Lead Sponsor: University of Washington

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 31

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (placebo)	HER-2/neu Intracellular Domain Protein	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.
Arm II (polysaccharide-K)	HER-2/neu Intracellular Domain Protein	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.
Arm I (placebo)	Laboratory Biomarker Analysis	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.
Arm I (placebo)	Pertuzumab	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.
Arm I (placebo)	Placebo	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.
Arm I (placebo)	Trastuzumab	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.
Arm II (polysaccharide-K)	Pertuzumab	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.
Arm II (polysaccharide-K)	Polysaccharide-K	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.
Arm II (polysaccharide-K)	Trastuzumab	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.
Arm II (polysaccharide-K)	Laboratory Biomarker Analysis	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Grade 3 or Higher Toxicity Per Study Arm.	Up to 4 months	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.

Secondary Outcome Measures

Name	Time	Method
Induction of Interferon (IFN)-Gamma Production and Cluster of Differentiation (CD)107a Expression in NK Cells, Via Flow Cytometry	Up to 16 weeks	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).