Phase 2 Study of Fulvestrant With and Without Entinostat in Postmenopausal Women With ER+ Advanced Breast Cancer

Entinostat (SNDX-275) inhibits mechanisms of resistance to hormone therapy in breast cancer
(BC) cells, thereby prolonging sensitivity of the cells to fulvestrant. Preclinical data has
demonstrated that entinostat can enhance fulvestrant sensitivity in hormone
receptor-positive BC in animal models. Thus, it is hypothesized that the addition of
entinostat to fulvestrant will provide clinical benefit to patients with locally advanced or
metastatic BC when compared to fulvestrant plus placebo.

Preliminary data from Phase 2 Study SNDX-275-0301 suggest patients with higher levels of
protein lysine acetylation who receive entinostat with exemestane potentially have improved
clinical outcomes (e.g., PFS, OS) when compared to patients with lower levels of protein
lysine acetylation. Thus, it is hypothesized that patients exposed to entinostat and who
demonstrate an elevated level of protein lysine acetylation will have an improved efficacy
outcome.

Inclusion Criteria:

- Patient is a female who is: Postmenopausal OR Pre/perimenopausal and: Received at
least one prior hormone therapy in combination with a luteinizing hormone-releasing
hormone (LHRH) agonist prior to study entry. Initiated on an LHRH agonist at least 28
days prior to study entry. Demonstrated ovarian estradiol suppression, defined as an
estradiol level within postmenopausal ranges per institutional guidelines, within 28
days immediately prior to study entry

- Patient has histologically or cytologically confirmed ER+ and/or progesterone
receptor-positive (PR+) BC at initial diagnosis or on subsequent biopsy. With regard
to hormone receptor status, staining of ≥1% cells is considered positive. Receptor
status may have been determined at any time prior to randomization and from any site
(i.e., primary, recurrent, or metastatic)

- Patient experienced PD within 28 days before initiating study treatment and has been
deemed eligible for treatment with fulvestrant

- Patient has evidence of locally advanced or metastatic disease, based on imaging
studies (bone scan, CT, MRI) within 28 days before initiating study treatment

- Patient completed any prior radiotherapy ≥2 weeks prior to receiving the first dose
of study treatment and has recovered from any radiation-related toxicity

- Patient may have received 1 prior chemotherapy regimen for metastatic disease
provided treatment was completed ≥3 weeks prior to randomization. Prior chemotherapy
in the adjuvant or neoadjuvant setting is also allowed

- Patient is willing and able to provide or assist study personnel in accessing slides
from prior biopsies

- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Patient has the following laboratory parameters: a. Hemoglobin (Hgb) ≥9.0 g/dL;
unsupported platelet count ≥100×10P9P/L; and absolute neutrophil count (ANC)
≥1.5×10P9P/L without the use of hematopoietic growth factors; b. Creatinine ≤2.0
mg/dL; c. Total bilirubin <1.5 x institutional upper limit normal (≤3 mg/dL in case
of Gilbert's syndrome); d. Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤2 x institutional upper limit of normal; unless elevation is
due to metastatic disease to the liver, in which case ALT and AST must be within 5.0
x institutional upper limit of normal

- Patient is able to swallow tablets

- Patient is able to understand and give written informed consent and comply with study
procedures

Exclusion Criteria:

- Patient has rapidly progressive or life-threatening metastases (visceral crisis)

- Patient has HER2-positive (HER2+) disease, as defined by the 2013 American Society of
Clinical Oncology (ASCO)/College of American Pathologists (CAP) recommendations for
HER2 testing in BC (see
http://www.asco.org/quality-guidelines/recommendations-human-epidermal-growth-factor-receptor-2-testing-breast-cancer), or has unknown HER2 status

- Patient previously received treatment with entinostat or any other HDAC inhibitor,
including valproic acid

- Patient has had previous treatment with fulvestrant or other selective estrogen
receptor down-regulator (SERD) in the metastatic setting; such treatment may have
been given in the adjuvant setting

- Patient has an allergy to benzamide or inactive components of the study drug

- Patient has a history of allergies to any active or inactive ingredients of
fulvestrant

- Patient has a concomitant medical condition that precludes adequate study treatment
compliance or assessment, or increases patient risk, in the opinion of the
Investigator, such as but not limited to:

1. Myocardial infarction or arterial thromboembolic event within 6 months prior to
Baseline or severe or unstable angina, New York Heart Association (NYHA) Class
III or IV disease (see Appendix 2), or a QTc interval >470 msec.

2. Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or
uncontrolled systemic infection

3. Another active cancer (excluding adequately treated basal cell carcinoma or
cervical intraepithelial neoplasia [CIN] / cervical carcinoma in situ or
melanoma in situ). Prior history of other cancer is allowed, as long as there is
no active disease within the prior 5 years

- Patient is currently receiving treatment with any agent listed on the prohibited
medication list such as valproic acid or other systemic cancer agents

- Patient initiated oral bisphosphonates within 7 days prior to study drug

- Patient has moderate or severe hepatic impairment (i.e., Child-Pugh score B or C)

- Patient has brain or leptomeningeal metastases