Pembrolizumab, Tamoxifen Citrate, and Vorinostat in Treating Patients with Hormone Receptor Positive Stage IV Breast Cancer

Inclusion Criteria

• Pre and postmenopausal women or men with stage IV estrogen receptor positive (ER+) breast cancer histological or cytological confirmation * ER-positive tumors ** Progressed after at least one line of hormonal therapy ** Any number of prior chemotherapy in the metastatic setting ** Any number of prior hormonal therapies * ER-negative tumors ** PD-L1 low, high or unknown ** Progression after prior PD-1 or PD-L1 inhibitors allowed ** HER2 positive or negative
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Understand and voluntarily sign an informed consent prior to any study-related assessments or procedures are conducted and are able adhere to the study visit schedule and other protocol requirements
• Consent to paired tumor biopsy, for accessible tumors
• Measureable tumor by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v.) 1.1
• Archived tumor tissue (minimum of 8 slides for paraffin-embedded tumor tissue) for assessment of tumor-based biomarkers and immune score is required for eligibility
• Per good clinical practice, any toxicity related to prior therapies that, in the opinion of the investigator, would potentially be worsened with anti-programmed death 1 (PD1) therapy should be resolved to less than grade 1
• Within 14 days of study start: Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Within 14 days of study start: Hemoglobin (Hgb) >= 9 g/dL (may transfuse if clinically indicated)
• Within 14 days of study start: Platelets (plt) >= 100 x 10^9/L
• Within 14 days of study start: Potassium within normal range, or correctable with supplements
• Within 14 days of study start: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit normal (ULN) or =< 5.0 x ULN if liver tumor is present
• Within 14 days of study start: Serum total bilirubin =< 1.5 x ULN
• Within 14 days of study start: Serum creatinine =< 1.5 x ULN, or 24-hr clearance >= 60 ml/min; and
• Females of child-bearing potential (defined as a sexually mature women who): * Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or, * Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months) * Must have negative serum pregnancy test within 7 days before starting study treatment in females of childbearing potential (FCBP) and willingness to adhere to acceptable forms or birth control (a physician- approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; barrier contraceptive with spermicide; or vasectomized partner)
• Male subjects with female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study

Exclusion Criteria

• Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• 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 and may qualify for the study * Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Patients may continue on ovarian suppression
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Any condition that confounds the ability to interpret data from the study
• Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated with whole body radiation therapy (WBXRT) and are stable for 6 weeks are allowed; (gamma or cyber knife treated lesions may enroll 2 weeks after completion if toxicities are resolved and no longer requiring steroids, patients with asymptomatic brain metastases are allowed after discussion with the study sponsor)
• Persistent diarrhea or malabsorption >= National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management
• Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure
• Prior systemic cancer-directed treatments or investigational modalities =< 5 half-lives or 4 weeks, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy (except alopecia)
• Has an active auto-immune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopia would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• 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
• Active and ongoing steroid use, except for non-systemically absorbed treatments (such as inhaled or topical steroid therapy for asthma, chronic obstructive pulmonary disease [COPD], allergic rhinitis)
• Major surgery =< 2 weeks prior to starting a study drug or who have not recovered from side effects of such therapy
• Known hypersensitivity to pembrolizumab or any of its insipients
• Has received a live vaccine within 30 days prior to the first dose of trial treatment