A Vaccine (VRP-HER2) and Pembrolizumab in Treating Patients with Locally Recurrent or Metastatic HER2-Overexpressing Breast Cancer

Inclusion Criteria

• Histologically-confirmed breast cancer that is metastatic or locally recurrent (7th edition of the American Joint Committee on Cancer [AJCC] TNM system) with HER2/neu overexpression by immunohistochemistry (2+, 3+) or fluorescence in situ hybridization (FISH)+ per American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines and receiving trastuzumab plus pertuzumab (determined by their physician)
• Have undergone treatment with trastuzumab plus pertuzumab (as selected by their attending physician) for at least 3 weeks prior to initiation on this study
• Be willing and able to provide written informed consent/assent for the trial. Informed consent will be obtained from the patient prior to performing any study-related procedures, including screening visits. Available computed tomography (CT) scans and bone scans performed as standard of care prior to signing consent can be used to fulfill eligibility requirements if they were performed within 4 weeks of the first dose of study drug(s). Available multigated acquisition scan (MUGA), echocardiogram, and electrocardiogram (EKG) performed as standard of care prior to signing consent can be used to fulfill eligibility requirements if they were performed within 8 weeks of the first dose of study drug(s)
• Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade =< 1 (with the exception of grade 2 alopecia, grade 2 neuropathy and grade 2 fatigue)
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Normal cardiac function defined as either a MUGA or echocardiogram (ECHO) with left ventricular ejection fraction (LVEF) in normal institutional range (MUGA 50%; ECHO 55%)
• Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 7 days of treatment initiation)
• Platelets >= 100,000/mcL (performed within 7 days of treatment initiation)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 7 days of treatment initiation) without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (performed within 7 days of treatment initiation) (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN (performed within 7 days of treatment initiation) for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (performed within 7 days of treatment initiation)
• Albumin >= 2.5 mg/dL (performed within 7 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (performed within 7 days of treatment initiation) unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 7 days of treatment initiation) unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Ability to return to Duke University Medical Center for adequate follow-up as required by this protocol

Exclusion Criteria

• Patients in this study, may not receive cytotoxic chemotherapy, anti-estrogen therapy, targeted small molecule therapy, or radiation therapy in the 3 weeks before the first infusion of pembrolizumab, during the injection period for VRP-HER2 and infusion period for pembrolizumab or for at least 2 weeks after booster immunization with VRP-HER2 (arm 1) or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has estrogen receptor (ER) and or progesterone receptor (PR) positive breast cancer
• Patients may have received prior radiation including for brain metastases
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Prior history of autoimmune thyroiditis or vitiligo is permitted
• Has a known history of active TB (Bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirements of steroid treatment for at least 14 days prior to the first dose of study treatment
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has history of (non-infectious) pneumonitis that required steroids or active, noninfectious pneumonitis
• Has an active infection requiring systemic therapy or systemic use of antimicrobials within 72 hours prior to the first study treatment
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed