A Study Of Pembrolizumab In Combination With Trastuzumab-DM1

This research study is a Phase I clinical trial, which tests the safety of an investigational
intervention and also tries to define the appropriate dose of the investigational
intervention to use for further studies. "Investigational" means that the intervention is
being studied. It also means that the FDA (U.S. Food and Drug Administration) has not
approved the combination of Pembrolizumab and T-DM1 for use in patients, including people
with your type of cancer.

This study will determine what amount (or dose) of Pembrolizumab and of T-DM1 is safe for
people to take and what effects, good or bad, this combination may have on participants and
their disease.

The FDA has not approved Pembrolizumab for this specific disease but it has been approved in
the United Sates for the treatment of other types of cancer.

The FDA has approved Trastuzumab emtansine (T-DM1) as a treatment option for this type of
breast cancer

The combination of Pembrolizumab and T-DM1 is investigational. It is thought that together
these drugs to help get the immune system to attack tumor cells and kill cancer cells that
have the HER2 protein. However, it is not known if giving the two study drugs at the same
time will have a better anti-cancer effect than giving each treatment on its own.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed invasive breast cancer,
with stage IV disease. Patients without pathologic or cytologic confirmation of
metastatic disease should have unequivocal evidence of metastasis from physical
examination or radiologic evaluation.

- Either the primary tumor and/or the metastasis must have been tested for ER, PR and
HER2. Patient must have HER2+ breast cancer per ASCO CAP guidelines 2013.

- Prior chemotherapy:

- History of prior therapy with trastuzumab and a taxane, separately or in
combination, is required.

- Patients must have either received one line of prior therapy for metastatic
breast cancer, or have developed a disease recurrence during or within 6 months
after completing adjuvant therapy.

- No prior treatment with T-DM1 is allowed.

- Last dose of chemotherapy must be at least 21 days prior to registration.

- Prior biologic therapy:

--Patients must have discontinued all biologic or investigational therapy at least 21
days before registration.

- Prior radiation therapy:

- Patients may have received prior radiation therapy in either the metastatic or
early-stage setting.

- Radiation therapy must be completed at least 14 days prior to registration.

- In the dose de-escalation cohort: Subjects must have evaluable disease. In the
expansion cohort: Subjects must have at least one lesion that is not within a
previously radiated field that is measurable on computerized tomography (CT) or
magnetic resonance imaging (MRI) scan per RECIST version 1.1. Bone lesions are not
considered measurable by definition.

- Age is ≥18 years.

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,500/μl

- platelets ≥100,000/μl

- hemoglobin ≥9 g/dL

- total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for
patients with documented liver metastases.

- albumin >2.5mg/dL

- serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min

- INR/PT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as
long as PT or PTT is within therapeutic range of intended use of anticoagulants

- aPTT/PTT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as
long as PT or PTT is within therapeutic range of intended use of anticoagulants

- Participants enrolling in the dose expansion must have tissue that is amenable to
biopsy and be willing to undergo a fresh tissue biopsy at baseline. Participants who
undergo an attempted research biopsy procedure for the purpose of this protocol, and
in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in
order to continue on protocol.

- The effects of pembrolizumab on the developing human fetus are unknown. For this
reason and because tratuzumab, a component of T-DM1, is known to be teratogenic, women
of child-bearing potential and men of childbearing potential must agree to use
adequate contraception starting with the first dose of study therapy, for the duration
of study participation, and for an additional 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.

- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, the treating physician and principal
investigator should be informed immediately.

- While on the study, women should not breast-feed.

- Subjects of childbearing potential are defined as those who have not been
surgically sterilized and/or have had a menstrual period in the past year

- Female subject of child-bearing potential must have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If a
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.

- Patients on bisphosphonates may continue receiving bisphosphonate therapy during study
treatment.

- Left ventricular ejection fraction (LVEF) must be within institutional limits of
normal as assessed by echocardiogram or MUGA documented within 28 days prior to first
dose of study drug.

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- The subject has received another investigational agent within 21 days of the first
dose of study drug.

- The subject has received prior pembrolizumab or any other anti-PD-1 , anti-PD-L1, or
anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumab.

- Pre-existing neuropathy greater than or equal to grade 2.

- Hypersensitivity to pembrolizumab or T-DM1 or any of their excipients.

- The subject has any history or evidence of active, non-infectious pneumonitis or
interstitial lung disease.

- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with previously diagnosed brain metastases are eligible if they
have completed treatment at least one month prior to trial therapy initiation, are
neurologically stable with an absence of new neurological symptoms for at least 4
weeks prior to study entry, and have recovered from effects of radiotherapy or
surgery. Any corticosteroid use for brain metastases must have been discontinued
without the subsequent appearance of symptoms for ≥2 weeks before the first study
drug. Treatment for brain metastases may include whole brain radiotherapy,
radiosurgery, or a combination as deemed appropriate by the treating physician.

- Known carcinomatous meningitis.

- The subject has an uncontrolled intercurrent illness including, but not limited to,
uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia,
congestive heart failure (New York Heart Association Class III or IV; see Appendix B),
active ischemic heart disease, myocardial infarction within the previous six months,
uncontrolled diabetes mellitus, chronic liver or renal disease, or severe
malnutrition.

- Concurrent use of potent CYP3A4 inhibitors (see Appendix C), such as ketoconazole and
erythromycin, should be avoided during the study treatment with T-DM1.

- Active infection requiring intravenous antibiotics at cycle 1 day 1.

- Individuals with a history of a second malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
in situ, and non-melanoma cancer of the skin. Patients with other cancers diagnosed
within the past 5 years and felt to be at low risk of recurrence should be discussed
with the study sponsor to determine eligibility.

- The subject has a medical condition that requires chronic systemic steroid therapy or
any other form of immunosuppressive medication including disease modifiying agents, or
has required such therapy in the last 2 years. Replacement therapy (eg., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.

- The subject has an active autoimmune disease or a documented history of autoimmune
disease or syndrome that requires systemic steroids or immunosuppressive agents.

- The participant is positive for Hepatitis B surface antigen, or Hepatitis C RNA.

- Known HIV-positive participants. HIV-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
pembrolizumab. In addition, these participants are at increased risk of lethal
infections with bone marrow suppressive therapy, i.e. nab-paclitaxel. Appropriate
studies will be undertaken in participants receiving combination antiretroviral
therapy when indicated.

- The subject has received a live vaccine within 28 days of planned start of study
therapy. Note: seasonal influenza vaccines for infection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (i.e. Flu-Mist ®) are
live attenuated vaccines, and are not allowed