Abraxane® With or Without Mifepristone for Advanced, Glucocorticoid Receptor-Positive, Triple-Negative Breast Cancer

Primary Objective:

To compare the progression free survival (PFS) of patients treated with nab-paclitaxel +
placebo and patients treated with nab-paclitaxel + mifepristone.

Secondary Objectives:

1. To correlate percentage glucocorticoid receptor (GR) positivity in the most recent
metastatic tumor biopsy (or in primary tumor if only primary tumor is available) with
PFS in mifepristone and placebo groups.

2. To perform an exploratory assessment of overall response rate in both groups.

3. To collect information regarding overall survival in both treatment cohorts.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed breast cancer with stage
IV or unresectable stage III disease.

2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. To be
considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in
short axis when assessed by CT scan (CT scan slice thickness recommended to be no
greater than 5 mm).

3. Triple-negative breast cancer (defined as estrogen receptor (ER) and progesterone
receptor (PR) <10% positive; HER2 0-1+ by immuno-histochemistry (IHC) or fluorescence
in situ hybridization (FISH) ratio <2.0)

4. Patients must have tumor block or slides available for testing, and tumor must be
glucocorticoid receptor positive (defined as GR >10% moderate to strong staining by
central lab). A formalin-fixed, paraffin-embedded surgical or core needle biopsy
obtained from the primary tumor or from a metastasis and containing viable tumor
tissue is required for this evaluation. Fine needle aspirates or other alternative
cytology samples are not acceptable.

5. Patients may have received adjuvant chemotherapy and up to two prior chemotherapy for
metastatic or locally recurrent disease. No prior nab-paclitaxel or mifepristone
therapy for metastatic disease will be allowed.

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

7. Eastern Cooperative Oncology Group performance status ≤ 2 (Karnofsky ≥ 60%).

8. Patients must have normal organ and marrow function as defined below

- absolute neutrophil count >1,500 cells/mm3.

- platelets ≥100,000/mcL

- hemoglobin > 9.0 g/dL

- total bilirubin< 1.5 mg/dL

- alkaline phosphatase < 2.5 X upper limit of normal (ULN) or < 5 X ULN if bone
mets are present

- aspartate aminotransferase (AST) and Alanine transaminase (ALT) < 2.5 ULN or < 5
X ULN if liver mets are present

- adequate renal function: creatinine ≤ institutional upper limit of normal OR
creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal.

- international normalized ratio (INR) < 1.5

9. 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 and while on study medication.

- Have a negative serum pregnancy test result at screening and agree to ongoing
pregnancy testing during the study dosing

10. Male subjects must practice true 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.

11. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE).

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

Exclusion Criteria:

1. Patients who are receiving any other investigational agents.

2. Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.

3. 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.

4. Patients with known brain metastases will be eligible as long as they have completed
radiation to the brain, and have been off of corticosteroid therapy for at least 7
days.

5. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to mifepristone or paclitaxel/nab-paclitaxel. Patients with a history of
mild infusion reactions with paclitaxel who were able to continue to receive
paclitaxel with corticosteroid premedication will be eligible to participate, as these
cases were likely related to cremaphor and not paclitaxel.

6. 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.

7. 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.

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

9. 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.

10. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with 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.

11. No history of long-term use of corticosteroids or concurrent short term use of
corticosteroids is allowed.