The PROMISE Study: Duavee in Women With DCIS

PRIMARY OBJECTIVES;

• To determine if CE/BZA reduces proliferation as measured by Ki-67 protein expression

Secondary Objectives:

- To determine if CE/BZA modulates expression of ERα, progesterone receptor (PR) and human
epidermal growth factor receptor 2 (HER-2).

- To determine if CE/BZA modulates a previously validated set of epithelial markers of
progression.

- To determine if TSECs will restore expression of the stromal marker CD36 and repress
pro-tumorigenic ECM proteins and soluble factors.

- To determine if a short intervention with CE/BZA results in any difference in Quality of
Life (QOL) as it relates to menopausal symptoms in postmenopausal women with DCIS.

- To determine if a short intervention with CE/BZA has a favorable side effect profile
compared with other endocrine therapy interventions using the validated Breast Cancer
Prevention Trial Eight Symptom Scale (BESS) questionnaire.

Exploratory Objectives

- To determine if CE/BZA alters expression of estrogen-modulated genes and elicits novel
ER dependent-gene signatures in breast epithelium

- To demonstrate that CE/BZA does not upregulate Anterior Gradient 2 (AGR2), a marker of
ERα agonist activity.

- To determine if CE/BZA will modulate some aspects of immune function as measured by a
switch to a M2-type pro-tumorigenic macrophage signature and an immunosuppressive T cell
signature.

- To determine if a short intervention with CE/BZA alters expression of estrogen-modulated
genes and elicits novel ER dependent-gene signatures in the breast stroma.

- To determine if CE/BZA affects plasma concentrations of BZA in patients with the
UGT1A1*28 gene polymorphism.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive conjugated estrogens/bazedoxifene orally (PO) once daily (QD) for 28
+/- 7 days in the absence of disease progression or unacceptable toxicity. Patients then
undergo surgery.

ARM II: Patients receive placebo PO QD for 28 +/- 7 days in the absence of disease
progression or unacceptable toxicity. Patients then undergo surgery.

Inclusion Criteria:

- Women must have newly diagnosed histologically confirmed estrogen receptor positive
(ER+) DCIS scheduled to undergo surgical therapy; the pathology report (signed
pathology report from attending pathologist) from each individual institution will be
used to determine eligibility; (Note: after the patient has completed the study and
the slides have been sent to Northwestern University [NU], our pathologists will
review the slides to confirm the diagnosis)

- DCIS suspicious for micro invasion is eligible on core biopsy; this is due to the fact
that many these patients will not have invasion on final pathology

- DCIS must be greater than or equal to 1 cm based on extent of calcifications, presence
of a mass on ultrasound OR enhancement on magnetic resonance imaging (MRI)

- DCIS must be at least 5 mm of DCIS on one single core; can be < 5 mm if DCIS is
identified on multiple cores (at least 2 cores)

- Women presenting after excision with positive margins are eligible; Ki-67,
cyclooxygenase 2 (Cox-2), cyclin-dependent kinase inhibitor 2A (P-16), expression in
immediately adjacent tissue is similar to what is found in DCIS Note: Positive margins
are defined as DCIS present at the inked margin or DCIS <1mm from the margin.

- Women must be postmenopausal (defined as no menstrual cycle for 12 months or surgical
history of bilateral salpingo-oopherectomy); postmenopausal women of all races and
ethnic groups are eligible to participate for this trial; men are not eligible

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dl

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate [SGPT]) =< 2.5 ×
institutional upper limit of normal

- Serum creatinine =< 1.5 x ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for
patients with creatinine levels above institutional normal

- Patients ability to swallow oral medication

- Ability to understand and the willingness to sign a written informed consent document
and comply with all procedures

Exclusion Criteria:

- Patients who are receiving any other investigational agents; a minimum of 4 weeks
wash-out period is required for eligibility; please contact Principal Investigator,
Dr. Swati Kulkarni for further clarification

- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers; patients are not considered to have a "currently active" malignancy if they
have completed therapy and are free of disease for >= 3 years

- History of allergic reactions/hypersensitivity attributed to compounds of similar
chemical or biologic composition to CE/BZA; (I.e. same class of drug as CE/BZA)

- Current HRT, SERM or Aromatase Inhibitor (AI) use. If yes, the wash-out period is
30 days before diagnostic core needle biopsy.

Note: Local therapy (i.e. estrogen cream) will be permitted due to low systemic absorption
of estrogen.

Note: if patient is registered prior to completed washout, diagnostic core needle biopsy
date will need to be provided

- Confirmed current or past diagnosis of invasive breast cancer

- History of gynecologic malignancy that is estrogen dependent

- Patients with recurrent ipsilateral DCIS

- Active deep venous thrombosis, pulmonary embolism, retinal vascular thrombosis, and
any arterial thrombosis including stroke and myocardial infarction or history of these
conditions

- Known protein C, protein S, or anti-thrombin deficiency or other known thrombophilic
disorders

- Unexplained/undiagnosed abnormal uterine bleeding (concern for undiagnosed endometrial
cancer)

- Women who are pregnant or lactating, CE/BZA may cause fetal harm when administered to
a pregnant woman; if this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential
hazard to a fetus

- Patients receiving any medications or substances that are strong inhibitors or
inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) and uridine
5'-diphospho-glucuronosyltransferase (UGT) are ineligible; the wash out period for
such drugs is a minimum of 7 days or 5 half-lives

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements