Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients With Chest Wall Breast Cancer

Inclusion Criteria:

• Histologically proven, PDL1 (≥1%) positive and/or tumor infiltrating lymphocytes (TILs) positive (≥1%), locally advanced "chest wall" breast cancer (with or withoutdistant metastases), who have been treated with chemotherapy or radiation therapymay be eligible for this study. Patients with cutaneous metastases only (with orwithout evidence of primary tumor) are also eligible;

• Patients must have tissue accessible for serial biopsies;

• Expected survival of > 3 months;

• Be willing and able to provide written informed consent/assent for the trial. Thesubject may also provide consent/assent for Future Biomedical Research. However, thesubject may participate in the main trial without participating in Future BiomedicalResearch. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samplescannot be provided (e.g. inaccessible or subject safety concern) may submit anarchived specimen only upon agreement from the Sponsor;

• Be 18 years of age on day of signing informed consent;

• Be a female or male subject with IBC with lymphangitic spread to the chest wall. ER,PgR and HER2 status determination is required for enrollment;

• Have provided tissue for PD-L1 biomarker analysis from a newly obtained core orexcisional biopsy of a tumor lesion (mandatory) and received permission forenrollment from the Core Lab based on the adequacy of the biopsy specimen. Repeatsamples may be required if adequate tissue is not provided;

• Have measurable metastatic disease based on irRECIST criteria as determined bycentral radiology review. Tumor lesions situated in a previously irradiated area areconsidered measurable, if progression has been demonstrated in such lesions. Note:The exact same image acquisition and processing parameters should be used throughoutthe study;

• Have a performance status of 0 or 1 on the ECOG Performance Scale. Assessment shouldbe performed within 10 days of treatment initiation;

• Female subjects of childbearing potential (Section 2.9.2) must be willing to use anadequate method of contraception as outlined in Section 2.9.2 - Contraception, forthe course of the study through 120 days after the last dose of study medication;

• Male subjects childbearing potential (Section 2.9.2) must agree to use an adequatemethod of contraception as outlined in Section 2.9.2- Contraception, starting withthe first dose of study therapy through 120 days after the last dose of studytherapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the subject;

• Female subjects of childbearing potential should have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required;

• Patients with hormone receptor-positive and/or HER2-positive breast cancer would beeligible for the study only if their disease is considered refractory to hormonal oranti-HER2 agents, respectively, and no further hormonal or anti-HER2 treatment isindicated;

• Demonstrate adequate organ function as defined in protocol, all screening labsshould be performed within 10 days of treatment initiation;

• Female subject of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required;

• Female subjects of childbearing potential (Section 5.7.2) must be willing to use anadequate method of contraception as outlined in Section 5.7.2 - Contraception, forthe course of the study through 120 days after the last dose of study medication.Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the subject;

• Male subjects of childbearing potential (Section 5.7.1) must agree to use anadequate method of contraception as outlined in Section 5.7.1- Contraception,starting with the first dose of study therapy through 120 days after the last doseof study therapy. Note: Abstinence is acceptable if this is the usual lifestyle andpreferred contraception for the subject.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 4 weeks of the first dose of treatment;

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to the first dose oftrial treatment;

• Has a known history of active TB (Bacillus Tuberculosis);

• Hypersensitivity to pembrolizumab or any of its excipients;

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to studyDay 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse eventsdue to agents administered more than 4 weeks earlier;

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapywithin 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent. Note 1:Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and mayqualify for the study. Note 2: If subject received major surgery, they must haverecovered adequately from the toxicity and/or complications from the interventionprior to starting therapy.

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy or in situ cervical cancer;

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for at leastfour weeks prior to the first dose of trial treatment and any neurologic symptomshave 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. Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability;

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment;

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

• Has an active infection requiring systemic therapy;

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator;

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial;

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 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 andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.