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Pembrolizumab and Mifepristone in Treating Patients with Metastatic or Locally Advanced and Unresectable HER2-Negative Breast Cancer

Trial Status: Active

This phase II trial studies how well pembrolizumab and mifepristone works in treating patients with HER2-negative breast cancer that has spread to other places in the body, or to nearby tissues or lymph nodes and cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Hormone therapy using mifepristone may fight breast cancer by lowering the amount of progesterone and glucocorticoid the body makes. Giving pembrolizumab and mifepristone may work better in treating patients with HER2-negative breast cancer.

Inclusion Criteria

  • 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 computed tomography (CT) scan or caliper measurement on clinical exam or lymph node >= 15 mm in short axis
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 80,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine clearance >= 60 mL/min/1.73 m^2
  • International normalized ratio (INR) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as prothrombin time (PT) or partial thromboplastin time (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 (beta-human chorionic gonadotropin [hCG]) result at screening
  • For this trial, 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
  • 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: * 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 * Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR * 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: * Practice abstinence from heterosexual activity; OR * 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 Electronic Research Collection (ERC)s/Institutional Review Board (IRB)s; 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
  • Have diagnosis of triple negative breast cancer (defined as estrogen receptor [ER] < 1% by immunohistochemistry [IHC], progesterone receptor [PR] < 1% by IHC, Her 2 negative by American Society of Clinical Oncology [ASCO] College of American Pathologists [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)
  • 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
  • Breastfeeding should be discontinued if the mother wishes to participate in this study
  • Human deficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • 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. hepatitis B surface antigen [HBsAg] reactive), or hepatitis C (e.g. hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] 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 10 mg 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


University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Rita Nanda
Phone: 773-834-2756
NorthShore University HealthSystem-Evanston Hospital
Contact: Michele Britto
Phone: 847-570-2109


I. Determine the overall response rate based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of the combination of pembrolizumab and mifepristone in the different subtypes of breast cancer (hormone receptor positive, triple-negative).


I. Determine the safety and tolerability of the combination of pembrolizumab and mifepristone.

II. Determine the overall response rate based on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) of the combination of pembrolizumab and mifepristone in the different subtypes of breast cancer (hormone receptor positive, triple-negative).


I. Determine change in tumor microenvironment in pre and on treatment biopsies by arm.

II. Determine change in blood CD8/CD4 ratio pre and post treatment by arm.

III. Correlate PD-L1 expression with response to therapy in each cohort.


Participants receive pembrolizumab intravenously (IV) on day 1 and mifepristone orally (PO) once daily (QD) beginning one week prior to start of pembrolizumab and then on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 6 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Rita Nanda

  • Primary ID IRB17-0721
  • Secondary IDs NCI-2018-00004
  • ID NCT03225547