Mifepristone and Eribulin in Patients With Metastatic Triple Negative Breast Cancer or Other Specified Solid Tumors

There will be two parts to the study: Part 1, a dose escalation phase, in which the MTD and RP2D will be determined in up to 20 patients with metastatic breast or other specified solid tumors, regardless of receptor status; and Part 2, a dose expansion phase in which a preliminary estimate of efficacy will be made in an expansion group of up to 20 patients with glucocorticoid receptor-positive metastatic TNBC at the RP2D.

Treatment will be administered in 21-day cycles, with the exception of the first cycle, which will be of 28 days duration with a lead-in of 7 days dosing of mifepristone.

Cycle 1 (28-day cycle): Mifepristone administered orally (PO) with food once daily for 28 days. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on days 8 and 15.

Cycle 2 and beyond (21-day cycle): Mifepristone administered orally (PO) with food once daily for 21 days. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on days 1 and 8.

Enrollment in Part 2 of the study (dose expansion) will occur once the RP2D has been determined. Patients in the dose expansion study must have TNBC disease that is glucocorticoid receptor-positive (by immunohistochemistry [IHC]). Patients will be treated in repeated 21-day cycles until progression or another withdrawal criterion is met.

Part 1 of the study is complete. Part 2 of the study is ongoing.

Inclusion criteria

• Informed consent given prior to study-specific screening procedures
• ≥ 18 years old

Part 2, dose expansion:

• Diagnosis of TNBC: < 1% cells positive for ER/progesterone receptor, and HER2 IHC score of 0 or 1, or FISH HER2+ ratio of less than 1.8; patients with low ER IHC (> 1% but < 10% cells positive), but negative by genomic assay are eligible
• Inoperable metastatic or locally advanced unresectable disease
• Patients should have received a minimum of one, and up to five prior chemotherapy regimens
• Must have submitted a diagnostic FFPE tumor tissue sample to confirm tumor GR positivity. Tumor tissue may be from primary or metastatic lesion. In the absence of sufficient tissue to complete IHC, a tumor biopsy will be required.
• Tumor must be glucocorticoid receptor positive TNBC (≥10% positive cells by IHC of tumor biopsy)
• Must have measurable disease (RECIST v1.1) in at least one lesion not previously irradiated unless documented evidence of progression
• Patients with treated, stable brain metastases eligible providing treatment was ≥4 weeks prior to initiation of study drug, and baseline CT or MRI negative for new brain metastases. Must not require therapy with corticosteroids.
• ECOG performance status 0 or 1
• Must have adequate bone marrow and renal/hepatic function at the screening visit (≤7 days preceding the lab assessment):

i. ANC ≥ 1,500/mm3, without G-CSF

ii. Platelets ≥ 100,000/mm3, without transfusion

iii. Hemoglobin ≥ 9 g/dL, without transfusion support

iv. AST or ALT ≤ 3 × ULN

v. Total serum bilirubin ≤ 1.5 times ULN

vi. Serum creatinine ≤ ULN

vii. Potassium and magnesium levels within normal limits. If below the lower limit of normal, must have levels corrected by supplementation prior to starting study drug.

viii. albumin > 3.0 g/dL

• PT/aPIT ≤ 1.5 x ULN
• Disease-free period of > 3 years from any other previous malignancies, excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Female patients of childbearing potential must have a negative serum pregnancy test. Sexually active patients must be willing to use non-hormonal contraception, including condom use by male partner, and barrier method by the female partner during the treatment period and for at least 3 months after the last dose of the study drug. Females considered not of childbearing potential include those who have been in menopause > 2 years, or are surgically sterile (status post tubal ligation or hysterectomy).
• Must be able and willing to comply with the study visit schedule and study procedures.
• Able to take oral medications

Exclusion criteria

• Systemic cytotoxic therapies or radiotherapy ≤14 days prior to day 1 cycle 1
• Major surgery within 4 weeks, or minor surgery within 2 weeks prior to day 1 of cycle 1
• Endometrial bleeding
• For two weeks prior to day 1 cycle 1, administration of specified cytochrome P450 3A (CYP3A) inducers
• Patients who are taking simvastatin or lovastatin. Patients should be switched to alternative therapies a minimum of 2 weeks before starting study drug
• Patients who have been treated with an investigational agent <21 days prior to day 1 of cycle 1
• Concomitant use of biological agents including growth factors. Exception: 3- to 6-patient breast cancer cohort enrolled to explore the use of prophylactic growth-factor support of a 1.4 mg/m2 dose of eribulin.
• Patients who require treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g. immunosuppression after organ transplantation)
• History of significant cardiac disease. Includes second/third degree heart block; significant ischemic heart disease; mean QTc interval > 480 msec prior to study start; poorly controlled hypertension; congestive heart failure of NYHA Class II or worse
• Pregnant or breast-feeding
• Any other significant co-morbid conditions that would impair study participation or cooperation
• In Part 2, unable or unwilling to consent to provision of tumor tissue for GR assay