Study of Pembrolizumab and Mifepristone in Patients With Advanced HER2-negative Breast Cancer

Eligible patients will be treated with pembrolizumab on day 1 of every 21 day cycle, given at
a dose of 200 mg. Mifepristone 300mg PO will be administered daily starting the week prior to
pembrolizumab. Enrollment will be paused after the first 10 patients are enrolled in the
study for a safety evaluation. Once safety is confirmed, dose expansion cohorts will be
performed in parallel for each indication

- Hormone receptor positive, hormone refractory advanced breast cancer (n = 25-34)

- Triple-negative advanced breast cancer (n = 27-40) Mandatory pre- and on-treatment tumor
biopsies will be obtained in order to evaluate immunological changes in these tissues.

Cycle length is 21 days. Patients will be evaluated every 3 cycles until progression of
disease unless the patient is otherwise withdrawn from the study.

Inclusion Criteria:

Common to both cohorts

- Patients must have histologically confirmed breast cancer that is metastatic or
locally advanced and unresectable.

- Patients must have evaluable disease as defined by RECIST 1.1 with tumor lesion > 10
mm by CT scan or caliper measurement on clinical exam or lymph node ≥ 15mm in short
axis.

- ECOG performance status of 0 or 1.

- Age ≥ 18 years. Because no dosing or adverse event data are currently available on the
use of pembrolizumab in combination with mifepristone in patients < 18 years of age,
children are excluded from this study, but will be eligible for future pediatric
trials.

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥ 1,000/mcL

- platelets ≥ 80,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal

- creatinine clearance ≥ 60 mL/min/1.73 m2

- INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use on anticoagulant.

- Females of child-bearing potential (defined as a sexually mature woman who has not
undergone hysterectomy, bilateral oophorectomy, or who has not been naturally
postmenopausal for at least 24 consecutive months prior to study enrollment) must:

- Commit to abstinence from heterosexual contact or agree to use effective contraception
without interruption beginning at least 28 days prior to starting protocol therapy,
while on study medication, and for 6 months following the last dose of therapy.

- Have a negative serum pregnancy test (β -hCG) result at screening.

- Male subjects must practice abstinence or agree to use a condom during sexual contact
with a pregnant female or a female of childbearing potential while participating in
the study, during dose interruptions and for 6 months following protocol
discontinuation, even if he has undergone a successful vasectomy.

Contraception Mifepristone is an abortifacient agent with the potential for teratogenic
effects . Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is
not known if pembrolizumab has transient adverse effects on the composition of sperm.

For this trial, male subjects will be considered to be of non-reproductive potential if
they have azoospermia (whether due to having had a vasectomy or due to an underlying
medical condition).

Female subjects will be considered of non-reproductive potential if they are either:

1. postmenopausal (defined as at least 24 months with no menses without an alternative
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH)
level in the postmenopausal range may be used to confirm a post-menopausal state in
women not using hormonal contraception or hormonal replacement therapy. In the absence
of 12 months of amenorrhea, a single FSH measurement is insufficient.); OR

2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR

3. has a congenital or acquired condition that prevents childbearing.

Female and male subjects of reproductive potential must agree to avoid becoming pregnant or
impregnating a partner, respectively, while receiving study drug and for 120 days after the
last dose of study drug by complying with one of the following:

1. practice abstinence† from heterosexual activity; OR

2. use (or have their partner use) acceptable contraception during heterosexual activity.

Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):

- intrauterine device (IUD)

- vasectomy of a female subject's male partner

- contraceptive rod implanted into the skin

Combination method (requires use of two of the following):

- diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)

- cervical cap with spermicide (nulliparous women only)

- contraceptive sponge (nulliparous women only)

- male condom or female condom (cannot be used together)

- hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or
subcutaneous contraceptive injection

- Abstinence (relative to heterosexual activity) can be used as the sole method of
contraception if it is consistently employed as the subject's preferred and usual
lifestyle and if considered acceptable by local regulatory agencies and
ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal,
post-ovulation methods, etc.) and withdrawal are not acceptable methods of
contraception.

- If a contraceptive method listed above is restricted by local
regulations/guidelines, then it does not qualify as an acceptable method of
contraception for subjects participating at sites in this country/region.

Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to
participate in the study subjects of childbearing potential must adhere to the
contraception requirement (described above) from the day of study medication initiation (or
14 days prior to the initiation of study medication for oral contraception) throughout the
study period up to 120 days after the last dose of trial therapy. If there is any question
that a subject of childbearing potential will not reliably comply with the requirements for
contraception, that subject should not be entered into the study.

- Ability to understand and the willingness to sign a written informed consent document.

- Any number of prior therapies is allowed.

- Patients must consent to pre and on treatment research biopsies

- Patients must have measurable disease.

Cohort 1 (TNBC):

- Have diagnosis of triple negative breast cancer (defined as ER < 1% by IHC, PR < 1% by
IHC, Her 2 negative by ASCO CAP guidelines).

- Patients with TNBC may be enrolled in dose expansion cohort A with any number of prior
lines of therapy (patients will be allowed to enroll in frontline setting).

Cohort 2 (HR+):

- Have a diagnosis of ER+ breast cancer (defined as ER > 1% by IHC).

- Patients with ER+ breast cancer must have progressed on at least 2 lines of endocrine
therapy.

Exclusion Criteria:

- 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.

- Patients who have had chemotherapy or radiotherapy prior to entering the study must
have recovered from adverse events to Grade 1.

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 agent, or
mifepristone

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging at least 4 weeks prior to first
dose of trial treatment and any neurologic symptoms have returned to baseline), have
no evidence of new or enlarging brain metastases, and are not using steroids for at
least 7 days prior to treatment.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab or mifepristone

- Uncontrolled intercurrent medical or psychiatric illness that would limit compliance
with study requirements.

- Pregnant women are excluded from this study because Mifepristone is an abortifacient
agent with the potential for teratogenic effects.

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with Mifepristone, breastfeeding should be
discontinued if the mother wishes to participate in this study.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with pembrolizumab and/or mifepristone.
In addition, these patients are at increased risk of lethal infections when treated
with marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has evidence of active, non-infectious pneumonitis

- Has an active infection requiring intravenous systemic therapy

- Has received a live vaccine within 30 days prior to first dose of therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines are live attenuated vaccines, and
are not allowed.

- Has a known human immunodeficiency virus (HIV), known active Hepatitis B (e.g. HBsAg
reactive), or Hepatitis C (e.g. HCV RNA [qualitiative] is detected) infection.

- Long term or concurrent use of corticosteroid therapy other than for premedication or
supportive care use as detailed in the protocol. Physiologic doses of steroids (e.g.
equivalent to or less than oral prednisone 10mg daily) are allowed and do not require
approval.

- Mifepristone can both inhibit CYP3A4 and induce CYP3A4. Addition of mifepristone to a
pre-existing drug regimen may cause a mild and temporary increase in plasma drug
concentration of drugs with significant CYP3A4 metabolism. Medications that are strong
inducers of CYP3A4 such as carbamazepine, oxcarbazepine, phenobarbital, phenytoin,
primidone, rifabutin, rifampin, rifapentine, St. John's Wort may decrease plasma
mifepristone levels. Strong CYP3A4 inhibitor medications are expected to cause the
largest increases in plasma mifepristone concentrations.

Mifepristone may increase the plasma drug concentration of concomitant medications with
metabolism mediated by CYP2C9/CYP2C8. Drugs with the largest increases will be those whose
metabolism is largely or solely mediated by CYP2C9/2C8 and include: Non-steroidal
Anti-inflammatory drugs (NSAIDs) and warfarin.