Pembrolizumab in High-risk Ductal Carcinoma in Situ (DCIS)

This study will include 3 dose cohorts using a 3+3 cohort dose escalation design (see figure
1) followed by a 4th cohort at the maximum tolerated dose. Unless a dose limiting toxicity
(DLT), defined any grade 3 or 4 toxicity, is observed requiring expansion of a cohort or a
subject withdraws, 3 subjects will be enrolled into each cohort in the dose escalation phase.
Subjects, upon diagnosis with high risk DCIS, will be offered 2 doses of pembrolizumab
injected intralesionally (IL) 3 weeks apart (+/- 1 week) with surgery 3 weeks (+/- 2 weeks)
after the 2nd dose. The subject will then undergo the surgical treatment as determined by the
surgeon and the subject (partial mastectomy or mastectomy). The primary objective of this
phase of the study will be safety and feasibility of intralesional injection of
pembrolizumab. The maximum tolerated dose will be used in the expansion phase. The expansion
cohort will have a target enrollment of 30 subjects randomized to either the control group or
the treatment group. 10 subjects will be randomized to the control group and 20 subjects will
be randomized to the treatment group. The control group will proceed to surgery alone
following the diagnosis of high risk DCIS. The treatment group will receive 2 doses of
intralesional pembrolizumab 3 weeks apart (+/- 1 week) prior to surgery. All subjects in the
expansion cohort will also undergo a baseline MRI at diagnosis and undergo a 2nd MRI prior to
surgery. Baseline and pre-surgical MRI images will be evaluated for changes in tumor volume.

Inclusion Criteria:

- Plan on having surgical treatment to remove the lesion

- Have at least 2 of the following high risk features associated with her DCIS -
high-grade (grade II-III), palpable mass, hormone receptor negative (less than 1%),
Her2 positive, young age (less than 45 years old), and large size (greater than 5 cm)

- Patients with a history of tamoxifen and/or aromatase inhibitor use for treatment or
prevention are eligible but should discontinue these medications at least 2 weeks
prior to starting this trial

- Be willing and able to provide written informed consent/assent for the trial.

- Be >=18 years of age on day of signing informed consent.

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

- Demonstrate adequate organ function as defined in Table 1 Adequate Organ Function
Laboratory Values

- All screening labs should be performed within 10 days of treatment initiation.

- Hematological 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 (within 7
days of assessment)

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

- Hepatic Serum total bilirubin <=1.5 xULN OR Direct bilirubin <= ULN for subjects with
total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) <= 2.5 X ULN Albumin
>=2.5mg/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

- 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.

- Female subjects of childbearing potential should be willing to use 2 methods 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.

Exclusion Criteria:

- 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.

- Is not interested in surgical treatment of her DCIS

- Has invasive breast cancer

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients.

- 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
(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.

- Has history of/active pneumonitis that required/is requiring steroid treatment or had
history of/active interstitial lung disease. Has an 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.

- 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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.