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

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

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.

Study Overview

• Status: Completed
• Conditions: Stage IV Breast Cancer; Recurrent Breast Carcinoma; HER2/Neu Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Placebo; Biological: HER-2/neu Intracellular Domain Protein; Biological: Pertuzumab; Biological: Trastuzumab; Biological: Polysaccharide-K

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo; Given PO; Other Names: placebo therapy; PLCB; sham therapy; Biological: HER-2/neu Intracellular Domain Protein; Given ID; Other Names: HER-2 ICD Peptide; HER-2/neu ICD Protein; HER2 ICD; HER2 Intracellular Domain; Biological: Pertuzumab; Given per standard of care; Other Names: Perjeta; 2C4; 2C4 Antibody; MoAb 2C4; Monoclonal Antibody 2C4; rhuMAb2C4; RO4368451; Biological: Trastuzumab; Given per standard of care; Other Names: Herceptin; ABP 980; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; PF-05280014; rhuMAb HER2; RO0452317; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar PF-05280014
Experimental: Arm II (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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: HER-2/neu Intracellular Domain Protein; Given ID; Other Names: HER-2 ICD Peptide; HER-2/neu ICD Protein; HER2 ICD; HER2 Intracellular Domain; Biological: Pertuzumab; Given per standard of care; Other Names: Perjeta; 2C4; 2C4 Antibody; MoAb 2C4; Monoclonal Antibody 2C4; rhuMAb2C4; RO4368451; Biological: Trastuzumab; Given per standard of care; Other Names: Herceptin; ABP 980; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; PF-05280014; rhuMAb HER2; RO0452317; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar PF-05280014; Biological: Polysaccharide-K; Given PO; Other Names: PSK; Glycoproteins; Krestin; KS-2

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS		Up to 3 years
PFS		Up to 3 years
Change in Intermolecular Epitope Spreading Assessed by IFN-gamma Enzyme-linked Immunosorbent Spot Assay	IFN-γ ELISPOT assay will be used to evaluate T cell precursor frequency to specific breast tumor antigens. A positive immune response will be defined as a post-vaccination T cell precursor frequency >1:20,000 antigen-specific PBMCs. In patients with a baseline precursor frequency >1:20,000, a positive post-vaccination immune response will be defined as a 2-fold increase in antigen-specific PBMC. PBMC will be cryopreserved and subsequently be thawed at time of analysis.	Baseline to 12 months after completion of treatment
Change in Pro-inflammatory Serum Cytokine and/or Chemokines Assessed by Luminex Analysis		Baseline to 24 hours after completion of treatment
Change in Serum TGF-beta Levels Assessed by Enzyme-linked Immunosorbent Assay		Baseline to 12 months after completion of treatment

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI); National Center for Complementary and Integrative Health (NCCIH)

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2014
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: August 1, 2013
• First Submitted That Met QC Criteria: August 12, 2013
• First Posted (Estimate): August 14, 2013

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 15, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Interferon Inducers; Radiation-Protective Agents; Trastuzumab; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Pertuzumab; polysaccharide-K
• Other Study ID Numbers: 7866 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2013-01377 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 135; 7866/135; U19AT006028 (U.S. NIH Grant/Contract)