A Study Of Pembrolizumab In Combination With Trastuzumab-DM1

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 preg