PRIMARY OBJECTIVE:
I. To define the role of epigenetic immune priming in a biomarker enriched estrogen receptor
(ER)+ breast cancer population on the basis of overall response rate.
SECONDARY OBJECTIVES:
I. To assess duration of response (DOR) 24-week landmark progression-free survival (PFS:24).
II. Median PFS and overall survival (OS). III. Tumor responses will also be calculated by
Immune Related Response-Criteria (irRC).
EXPLORATORY OBJECTIVES:
I. Evaluation of biomarker target threshold on response rate (retrospective cut off of 20%
versus [vs] 10%).
II. To assess the ratio of effector T cells: regulatory T cells in blood and tumor biopsies
pre- and post-therapy.
III. To evaluate inflammatory T cell signature changes in blood and tumor biopsies pre- and
post-therapy.
IV. To evaluate changes in number of myeloid-derived suppressor cells (MDSCs) in peripheral
blood and tumor biopsies pre- and posttherapy.
V. To evaluate changes in histone acetylation in peripheral blood cells and tumor biopsies
pre- and post-therapy.
VI. Initial comparison to vorinostat-induced PD-1 in lymphocytes, PD-L1 modulation.
VII. Nanostring and 10 x sequencing and single cell immune phenotyping (on stored tissue for
successful arms only).
VIII. Impact of histone deacetylase (HDAC) inhibition of response to pembrolizumab vs.
pembrolizumab in biomarker enriched population.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, vorinostat
orally (PO) once daily (QD) for 4 days weekly, and tamoxifen PO QD on days 1-21. Cycles
repeat every 21 days in the absence of disease progression of unacceptable toxicity.
ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 and tamoxifen PO QD on days
1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable
toxicity.
After completion of study treatment, patients are followed up for 30 days and then every 12
weeks thereafter.
Inclusion Criteria:
- Pre and postmenopausal women or men with stage IV ER+ breast cancer histological or
cytological confirmation
- > 10% expression of PD-1/Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) dual
staining in Cluster of differentiation 8 (CD8) cells in tumor or blood
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
- Understand and voluntarily sign an informed consent prior to any study-related
assessments or procedures are conducted and are able to adhere to the study visit
schedule and other protocol requirements
- Consent to paired tumor biopsy
- Measurable tumor by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
- Per Good Clinical Practice, any toxicity related to prior therapies that, in the
opinion of the investigator, would potentially be worsened with anti-PD1 therapy
should be resolved to less than grade 1
- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L
- Hemoglobin (Hgb) >= 9 g/dL (may transfuse if clinically indicated)
- Platelets (plt) >= 100 x 10^9/L
- Potassium within normal range, or correctable with supplements
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit normal (ULN) or =< 5.0 x ULN if liver tumor is present
- Serum total bilirubin =< 1.5 x ULN
- Serum creatinine =< 1.5 x ULN, or 24-hr clearance >= 60 ml/min
- Females of childbearing potential (defined as 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 14 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;
intra-uterine device; barrier contraceptive with spermicide; or vasectomized
partner)
- All female and male participants must agree to use approved contraception during the
treatment period and for at least 18 weeks after the last dose of study treatment and
refrain from donating sperm during this period
Exclusion Criteria:
- Prior treatment with pembrolizumab or other PD-(L)1
- Any significant medical condition, laboratory abnormalities, which places the subject
at unacceptable risk if he/she were to participate in the study
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or current pneumonitis/ interstitial lung disease
- Has known active hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or
hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid (RNA) [qualitative] is
detected)
- Has a history of hepatitis B virus (HBV)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Symptomatic central nervous system metastases. Subjects with brain metastases that
have been previously treated and are stable for 6 weeks are allowed
- 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)
- Active autoimmune disease except for vitiligo or hypothyroidism
- 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
- Pregnant or breastfeeding
- Known human immunodeficiency virus (HIV) infection
- Known history of tuberculosis
- Known allergic reaction or intolerability to tamoxifen
- Patients with prior history of deep vein thrombosis (DVT)s must be on therapeutic or
preventive anticoagulation
