Reversing Therapy Resistance With Epigenetic-Immune Modification

Unique aspects of this study:

This is the first study to look at the response of hormone therapy resistance breast cancer
to epigenetic immune priming. It is also the first study to look at the combination of an
HDAC inhibitor (vorinostat), an anti-estrogen (tamoxifen) and a PD-1 inhibitor, pembrolizumab
in pre or postmenopausal patients with ER+ advanced breast cancer with progression on
multiple prior therapies.

Recent preclinical studies have further suggested that epigenetic priming may be even more
effective in ER-negative tumors that do not respond to immune check point inhibitors or have
low PD-1/PD-L1 expression. The goal of this study is to demonstrate that Vorinostat can
increase PD-1 and PD-L1 expression.

In a third arm the study will evaluate the role of epigenetic priming in tumors that are
ER-negative.

NOTE: Study no longer enrolling ER+ patients as of 12/29/2016. Now enrolling ER- patients.

Inclusion Criteria:

- Pre and postmenopausal women or men with stage IV 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.

- HER2 positive or negative

ER-Negative tumors

- PD-L1 low, high or unknown

- Progression after prior PD-1 or PD-L1 inhibitors allowed

- HER2 positive or negative

- 18 years or older

- 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 RECIST criteria 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-PD1 therapy
should be resolved to less than Grade 1

- Adequate organ function within 14 days of study start:

- Absolute neutrophil count (ANC) ≥ 1.5 X 109/L

- Hemoglobin (Hgb) ≥9g/dL (may transfuse if clinically indicated)

- Platelets (plt) ≥ 100 x 109/L

- Potassium within normal range, or correctable with supplements;

- AST and 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 ≥ 60ml/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; intra-uterine 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 and are stable for 6 weeks are allowed.

- Persistent diarrhea or malabsorption ≥ NCI 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, 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 breast feeding.

- Known Human Immunodeficiency Virus (HIV) infection and/or Hepatitis B or C positive.

- 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.

- Patients receiving medications or substances that are strong inhibitors or inducers
ofCYP450 enzyme(s) are ineligible. Lists including medications and substances known or
with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are
provided in Appendix 5.

- Pregnant women are excluded from this study because vorinostat, tamoxifen and PD-1 are
drug classes with the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother, breastfeeding should be discontinued if the mother is
treated with vorinostat, tamoxifen and PD-1 inhibitors.