A Randomized Phase II Study of Pembrolizumab, an Anti-PD (Programmed Cell Death)-1 Antibody, in Combination With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease

There will be a companion translational study operating concurrently with the study described
above. In this study, biomarker research to be performed on tumor biopsies and peripheral
blood samples will be performed to explore the immunologic and genomic mechanism of action
underlying treatment with pembrolizumab and carboplatin versus carboplatin alone. This
protocol includes tissue and blood correlative exploratory endpoints including changes in
tumor PD-L1 (programmed death ligand 1) gene expression, tumor and peripheral blood immune
composition and cytokine expression, plasma tumor DNA, circulating tumor cells, and tumor
myelocytomatosis (MYC) oncogene expression using tumor biopsy and peripheral blood testing
before and after treatment; correlations with these markers and disease control rate will be
assessed.

Inclusion Criteria:

1. Advanced breast cancer with locally recurrent chest wall disease not amenable to
surgical excision.

1. Distant sites of disease are allowed

2. Prior radiation to the chest wall is not required

2. The following disease subtypes are eligible:

1. Triple negative disease (defined as ER < 10%, PR < 10%, HER2 negative)

2. Hormone receptor positive, HER2 negative disease with evidence of progression on
at least two prior lines of hormone therapy. HER2 positive disease with c.
evidence of disease progression on trastuzumab, pertuzumab, ado trastuzumab
emtansine (T-DM1) and oral tyrosine kinase inhibitor unless contraindicated with
no other HER2 targeted therapy options available (patients in this category will
be classified by ER status).

i. Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ
hybridization (ISH) or fluorescence in situ hybridization (FISH) or
immunohistochemistry (IHC) methodology using standard criteria.

ii. Cardiac function must be determined within 4 weeks of study entry to be >=
institutional lower limit of normal (LLN) using echo or multiple gated acquisition
scan (MUGA)

3. Any number of prior lines of therapy are allowed

a. Prior platinum based therapy is allowed in the following settings: i. Treatment in
the neoadjuvant and/or adjuvant setting without clear progression of disease ii.
Treatment in the metastatic setting without clear progression of disease.

4. At least two weeks from last systemic therapy for breast cancer, with recovery of all
treatment related toxicity to grade 1 or less. Subjects with ≤ Grade 2 neuropathy are
an exception to this criterion.

5. At least two weeks from last radiation therapy, with recovery of all treatment related
toxicity to grade 1 or less (excluding alopecia).

6. Prior CNS disease is allowed if stable for at least one month since whole brain
radiation therapy, and 2 weeks since stereotactic radiotherapy, and not requiring
steroids. Patients whose CNS disease was surgically treated may be enrolled if stable
for at least one month, and not requiring steroids.

7. Able to provide tissue from a newly obtained core or excisional biopsy of a chest wall
tumor lesion. Newly-obtained is defined as a specimen any time after the last systemic
or local therapy utilized to treat the disease. 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

8. Willing and able to provide written informed consent.

9. Greater than or equal to18 years of age on day of signing informed consent.

10. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
2

11. Adequate organ function as defined in Table 1 within 10 days of treatment initiation.

Table 1 Adequate Organ Function Laboratory Values

Hematological Absolute neutrophil count (ANC) ≥1,000 /microliter (mcL)

Platelets ≥100,000 / mcL

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

Renal Serum creatinine OR Measured or calculated* creatinine clearance (GFR can also
be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60
mL/min for subject with creatinine levels > 1.5 X institutional ULN

Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN

Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) ≤
2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

Albumin >2.5 mg/dL

Coagulation 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

*Creatinine clearance should be calculated per institutional standard.

12. Female subjects 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.

13. Female subjects of childbearing potential should be willing to use an acceptable form
of birth control or be surgically sterile, or abstain from heterosexual activity for
the course of the study through 120 days after the last dose of study medication
(Reference Section 5.7.2). Subjects of childbearing potential are those who have not
been surgically sterilized or have not been free from menses for > 1 year.

14. Male subjects should 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.

Exclusion Criteria:

1. Treatment with an investigational agent within 4 weeks of the first dose of treatment.

2. A diagnosis of immunodeficiency or is currently receiving systemic steroid therapy at
any dose or is receiving any other form of immunosuppressive therapy. Steroid therapy
is not allowed within 7 days prior to the first dose of trial treatment. However,
topical and intranasal corticosteroids are allowed, and not an exclusion for
participation.

3. Known active TB (Bacillus Tuberculosis). Patients with a distant history of
tuberculosis that was appropriately treated and have no evidence of active infection
are eligible to participate. Patients with a history of latent tuberculosis that was
appropriately treated are also eligible to participate.

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Hypersensitivity to carboplatin or cisplatin

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 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.

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.

7. 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.

8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.

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

10. Have history of/active pneumonitis requiring treatment with steroids or history
of/active interstitial lung disease.

11. Has an active infection requiring systemic therapy.

12. 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.

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

14. 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.

15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has
been on any prior Merck MK-3475 (pembrolizumab) studies.

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

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

18. 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.