The primary objective of this phase II study is to determine whether pembrolizumab increases
the tumor infiltrating and peripheral blood immune response to the VRP-HER2 vaccine. The
investigators hypothesize that HER2 specific T cell responses and anti-tumor immunity induced
with HER2 vaccination will be augmented by concurrent anti-PD-1 antibody therapy.
The investigators will additionally determine whether the administration of pembrolizumab is
safe in patients with recurrent or metastatic HER2+ cancers who are receiving the anti-HER2
vaccine VRP-HER2.
There will be an initial Safety Arm (n=3) during which subjects will receive the VRP-HER2
immunizations plus pembrolizumab and if there is no dose limiting toxicity in the Safety Arm,
subjects will then be randomized 1:1:1 into 3 arms (n=12 per arm). Subjects with metastatic
HER2 overexpressing breast cancer receiving trastuzumab and pertuzumab will continue these
antibodies. They will undergo a biopsy of their tumor and peripheral blood draw for immune
cell analyses and be assigned to the applicable arm of the study. Arm A will consist of the
the VRP-HER2 immunizations; Arm B will consist of pembrolizumab; Arm C will consist of the
VRP-HER2 immunizations plus pembrolizumab. Tumor biopsies and peripheral blood draws will be
performed following the course of immunizations.
Inclusion Criteria:
- Have undergone treatment with trastuzumab plus pertuzumab for at least 3 weeks prior
to initiation on this study.
- Be willing and able to provide written informed consent/assent for the trial.
- Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical
procedures to NCI CTCAE (version 4.03) Grade ≤ 1 (with the exception of grade 2
alopecia, grade 2 neuropathy and grade 2 fatigue);
- Be >=18 years of age on day of signing informed consent.
- Have measurable disease based on RECIST 1.1.
- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion.. Subjects for whom newly-obtained samples cannot be provided may submit
an archived specimen only upon agreement from the Sponsor.
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
- Normal cardiac function defined as either a MUGA or ECHO with LVEF in normal
institutional range.
- Demonstrate adequate organ function as defined below:
System Laboratory Value Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 /
mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency
Serum creatinine OR Measured or calculated creatinine clearance
- 1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels >
1.5 X institutional ULN
Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR≤ 5 X ULN for subjects
with liver metastases Albumin >2.5 mg/dL International Normalized Ratio (INR) or
Prothrombin Time (PT)
- 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN 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.
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.
- 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.
- Has ER and or PR positive breast cancer.
- Patients may have received prior radiation including for brain metastases.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least 3 months
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment.
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapyor 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 active autoimmune disease that has required systemic treatment in the past 2
years.
- Has history of (non-infectious) pneumonitis that required steroids or active,
non-infectious 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.
- Hypersensitivity to pembrolizumab or any of its excipients.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is
detected).
- Has received a live vaccine within 30 days of planned start of study therapy.
