Preoperative Testing of the Anti-Progesterone Mifepristone in Early Stage Breast Cancer

Sponsor

University of California, San Diego (Other)

Overall Status

Terminated

CT.gov ID

NCT01138553

Collaborator

(none)

Enrollment

Location

Arm

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to identify the group of women with early stage breast cancer most likely to benefit from treatment with the selective progesterone receptor modulator (SPRM) mifepristone. This will be done by treating women briefly prior to planned surgery and examining the decrease in growth rate (measured by Ki-67 immunohistochemistry) in tumor samples taken before and after exposure to mifepristone.

Condition or Disease	Intervention/Treatment	Phase
Invasive Breast Cancer Ductal Carcinoma in Situ	Drug: Mifepristone	Early Phase 1

Detailed Description

Secondary objectives of this study include; (1) Measuring objective response in tumor size with treatment, (2) Establishing the safety and tolerability of short term mifepristone exposure in early stage breast cancer patients, and (3) Performing exploratory studies of expression of related targets following drug exposure.

Anti-estrogen therapy has been a mainstay of breast cancer treatment for over three decades. It is highly effective and has modest toxicity, certainly in comparison to chemotherapy. The selective estrogen receptor modulator tamoxifen has the longest history but a number of aromatase inhibitors and the anti-estrogen fulvestrant are also in widespread use along with ovarian ablation for pre-menopausal women. Given the success of this approach, and the highly analogous parallel progesterone signal, it is unfortunate that anti-progesterone therapy has not been similarly pursued. Additionally, data from the Woman's Health Initiative trial reveal a potentially significant role for progesterone in breast cancer development and growth. Healthy postmenopausal women treated with the combination of estrogen and progesterone over a 5 year period were 24% more likely to develop invasive breast cancer and had larger tumors at diagnosis. Notably this effect was not seen in post-hysterectomy women treated with estrogen alone over nearly 7 years. In fact a non-statistically significant reduction in breast cancer incidence was observed with estrogen alone.

The anti-progesterone mifepristone has been found to reduce proliferation in normal breast tissue. Even a low dose of mifepristone (50mg every other day for 3 months) demonstrated a statistically significant reduction in breast cell proliferation (measured by Ki-67 immunohistochemistry).

Higher doses of mifepristone, 200mg daily, have been used in patients with metastatic breast cancer for durations of almost 2 years without serious toxicity. Response rates were only 11% but no grade 4 or 5 toxicities occurred. Some grade 3 toxicities occurred, including lethargy, nausea, vomiting, and skin rash. These rashes resolved with temporary discontinuation of drug and did not recur when drug was resumed.

As a whole these data strongly support research into anti-progesterone therapy for early stage breast cancer. To our knowledge this is the first such study.

Study Design

Study Type:

Interventional

Actual Enrollment :

4 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Biomarker Study of Mifepristone in Early Stage Breast Cancer

Actual Study Start Date :

Jun 1, 2010

Actual Primary Completion Date :

Jun 1, 2014

Actual Study Completion Date :

Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mifepristone	Drug: Mifepristone 200mg capsules daily for 5-28 days

Arm

Intervention/Treatment

Experimental: Mifepristone

Drug: Mifepristone

200mg capsules daily for 5-28 days

Outcome Measures

Primary Outcome Measures

Change in proliferation by Ki-67 immunohistochemistry. [5-30 days]

Secondary Outcome Measures

Tumor size [5-30 days]
Expression of related targets following mifepristone exposure [5-28 days]
RNA-seq will be used to evaluate expression of steroid receptor isoform expression following drug exposure. These data will be compared with response as measured by proliferation change and tumor size.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female identified as a candidate for primary resection of breast cancer (invasive or ductal carcinoma in situ) by a UCSD Breast Care Unit surgical oncologist
Subjects must agree to contact the study coordinator prior to starting any new medications, vitamins or herbals during, or for 2 weeks following, mifepristone use
Subjects must agree to abstain from alcohol use while on mifepristone
Age ≥18
ECOG performance status 0-1
Prior to starting mifepristone subjects must have a negative urine (βHCG combo with on-board control) or blood pregnancy test and must be using one of the following acceptable means of birth control prior to starting study drug; Barrier methods or surgically sterile (tubal ligation, hysterectomy or partner with confirmed vasectomy). Alternatively the subject must be one year post-menopausal defined as greater than 12 months without a menstrual cycle
Prior to starting mifepristone subjects must meet the following laboratory criteria; Granulocytes > 1.5E9/l (grade ≤ 1); Platelets ≥ 100E9/l; Hemoglobin > 10 g/dl (grade ≤ 1); Creatinine < 1.5x normal reference range (grade ≤ 1); SGOT, SGPT, alk phos ≤ 1x normal reference range; Total bilirubin < 1x normal reference range; Calcium < 11.5 mg/dl (grade ≤ 1); HBsAg = Negative; HCV Ab = Negative; INR < 1.5;
Subjects must provide written informed consent

Exclusion Criteria:

Not scheduled for surgery within 5 days of enrollment
Subjects must not be on any therapy to treat breast cancer prior to surgical resection, specifically medications or recent (within 1 month of diagnostic biopsy) withdrawal of estrogen containing medication (eg. hormone replacement therapy)
Subjects must not be on any medications, vitamins or herbals that are; potent inhibitors of cytochrome P450 CYP3A4, or sensitive substrates for cytochrome P450 CYP3A4
Subjects may not have any history of significant cardiovascular, renal or hepatic disease requiring ongoing medical therapy or clinical intervention
Subjects may not have a history of thrombophlebitis, thromboembolic disorder, or cerebral vascular disease.
Subjects may not have any known hypersensitivity to mifepristone
Subjects may not have a BMI > 39
Subjects may not have an IUD (Intrauterine contraceptive device), chronic adrenal failure, concurrent long term steroid therapy, history of allergy to mifepristone, hemorrhagic disorders or concurrent anticoagulant therapy, or inherited porphyrias