Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients

This is a non-randomized, multi-site, open-label Phase II trial for subjects with metastatic,
hormone receptor positive, HER2 negative breast cancer. The study will enroll 47 patients to
evaluate the anti-tumor activity of pembrolizumab with fulvestrant as measured by RECIST 1.1
tumor response and by progression free survival. We expect that if the immune response is
augmented by the addition of pembrolizumab, significant change in durability of response will
be noted.

Patients will be treated with pembrolizumab dosed at 200 mg intravenous infusion in
combination with standard fulvestrant 500mg intramuscular injection.

Inclusion Criteria:

- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.

- Men and women ≥ 18 years of age at the time of informed consent.

- ECOG Performance Status of 0 or 1 within 28 days prior to registration.

- Histologic or cytologic diagnosis of metastatic breast cancer (unless metastatic
disease is definitive from most recent scans)

- Has received no more than one line of prior hormonal therapy (other than fulvestrant)
or no more than one line of prior chemotherapy for advanced non-resectable/metastatic
disease. Combination therapy is considered as 1 regimen.

- Tumor is estrogen receptor positive (ER+) and/or (PR+), HER-2 negative (HER2-). ER and
PR positivity is defined as >1%. HER-2 negative is defined as by IHC (0, 1+) or FISH.
HER2 positive test result includes: Single-probe average HER2 copy number ≥6.0
signals/cell; Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2; copy number ≥4.0
signals/cell; Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2copy number <4.0
signals/cell; or Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number
≥6.0 signals/cell. Equivocal findings for IHC as 2+ should be reflexed to FISH.
Equivocal results by FISH may be considered with approval from the
Sponsor-Investigator.

- Measurable disease based on RECIST 1.1 within 28 days prior to registration. NOTE:
Bone-only disease is allowed and biopsy is required. To meet RECIST 1.1 criteria,
bone-only disease must have soft tissue component.

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
metastatic tumor lesion. NOTE: Newly-obtained is defined as a specimen obtained up to
6 weeks (42 days) prior to study registration. 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-Investigator.

- Normal cardiac function as determined by treating physician per institutional
standards via Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
performed within 28 days prior to registration.

- Prior chemotherapy or targeted therapy, no more than one line, must be completed at
least 28 days prior to registration and the subject must have recovered from all
reversible acute toxic effects of the regimen (other than alopecia) to ≤Grade 1 or
baseline.

- No more than one prior hormonal therapy (only aromatase inhibitors with or without
ovarian suppression or tamoxifen allowed) or radiation therapy must be completed at
least 14 days prior to registration and the subject must have recovered from all
reversible acute toxic effects of the regimen to ≤Grade 1 or baseline.

- Absolute Neutrophil Count (ANC) ≥ 1500/mm3

- Platelets ≥100,000 / mcL

- Hemoglobin (Hgb) ≥ 9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within
7 days of assessment)

- Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used
in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR

≥30 mL/min for subjects 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) International Normalized Ratio (INR) or
Prothrombin Time (PT)

- 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

≤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

- Females of childbearing potential must have a negative urine or serum pregnancy test
within 72 hours prior to study registration. If the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required.NOTE: Females are
considered of child bearing potential unless: they are postmenopausal; are surgically
sterile; or they have a congenital or acquired condition that prevents childbearing.
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

- Females and males of reproductive potential must be willing to abstain from
heterosexual activity or agree to use an adequate method of contraception as outlined
in the protocol. Hormonal contraceptives are contraindicated in this population and
are not allowed. Contraception will begin from the time of informed consent through
120 days after the last dose of study drug(s).

Exclusion Criteria:

- Is currently receiving an investigational agent or has received an investigational
agent or used an investigational device within 28 days of study registration.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to study registration.

Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual
hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis
not requiring systemic treatment, or conditions not expected to recur in the absence of an
external trigger.

NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form
of systemic treatment.

- Has a known history of active TB (Bacillus Tuberculosis). NOTE: TB testing is not
required.

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). NOTE:
HIV testing is not required.

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

NOTE: Hepatitis B and Hepatitis C testing is not required.

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 28 days prior to study
registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
events due to agents administered more than 28 days earlier.

- Has had prior chemotherapy, hormone therapy (other than fulvestrant), targeted small
molecule therapy, or radiation therapy for metastatic breast cancer within 14 days
prior to study registration and who has not recovered (i.e., ≤ Grade 1 or at baseline)
from adverse events due to a previously administered therapy. Prior fulvestrant, more
than one line of chemotherapy or more than one line of non-fulvestrant hormonal
therapy excludes participation.

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 study registration, as
determined by the enrolling physician.

- 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. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
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. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

- Has known history of, or any evidence of active, non-infectious pneumonitis.

- Has known history of, or any evidence of active interstitial lung disease, Class II-IV
congestive heart failure, or myocardial infarction within 6 months from randomization.

- Active infection requiring systemic therapy.

- 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.

- Breastfeeding during the projected duration of the trial, starting with the screening
visit through 120 days after the last dose of trial treatment.

NOTE: breast milk cannot be stored for future use while the mother is being treated on
study.

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

- Has received a live vaccine within 30 days of study registration. 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.