HER2 Vaccine + Pembrolizumab Phase II Trial
Detailed Eligibility Criteria

Entry Criteria

1.1.1 Diagnosis/Condition for Entry into the Trial

Histologically-confirmed breast cancer that is metastatic or locally recurrent (7th Edition of the AJCC TNM System) with HER2/neu overexpression by immunohistochemistry (2+,3+) or FISH+ per ASCO CAP guidelines and receiving trastuzumab plus pertuzumab (determined by their physician). Patients who are hormone receptor (ER, PR) positive or negative are permitted.

1.1.2 Subject Inclusion Criteria

In order to be eligible for participation in this trial, the subject must:

1. Have undergone treatment with trastuzumab plus pertuzumab (as selected by their attending physician) for at least 3 weeks prior to initiation on this study.

2. 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 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 MUGA, Echocardiogram, and 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).

3. Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical procedures to NCI CTCAE (version 5.0) Grade ≤ 1 (with the exception of grade 2 alopecia, grade 2 neuropathy and grade 2 fatigue);

4. Be ³ 18 years of age on day of signing informed consent.

5. 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.

6. Have a performance status of 0 or 1 on the ECOG Performance Scale.

7. Normal cardiac function defined as either a MUGA or ECHO with LVEF in normal institutional range (MUGA 50%; ECHO 55%)

8. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 7 days of treatment initiation. 

9. 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. 

10. Female subjects of childbearing potential (Section 5.6.2) must be willing to use an adequate method of contraception as outlined in Section 5.6.2 – 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.

1. Male subjects of childbearing potential (Section 5.6.2) must agree to use an adequate method of contraception as outlined in Section 5.6.2- 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.

1. Ability to return to Duke University Medical Center for adequate follow-up as required by this protocol.

1.1.3 Subject Exclusion Criteria

The subject must be excluded from participating in the trial if any of the following criteria are met:

1. Patients in this study, may not receive cytotoxic chemotherapy 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. 

2. Patients may have received prior radiation including for brain metastases.

3. 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.

4. 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.

5. Has a known history of active TB   (Bacillus Tuberculosis)

6. Hypersensitivity to pembrolizumab or any of its excipients.

7. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 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 3 weeks earlier.  Exceptions include trastuzumab, pertuzumab.

8. 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.

9. Has known active 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. 

10. 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.

11. Has history of (non-infectious) pneumonitis that required steroids or active, non-infectious pneumonitis.

12. Has an active infection requiring systemic therapy or systemic use of antimicrobials within 72 hours prior to the first study treatment

13. 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. 

14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

15. 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.

16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

17. Hypersensitivity to pembrolizumab or any of its excipients.

1. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

2. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

3. Has received a live vaccine within 30 days of planned start of study therapy.