Abraxane® With or Without Mifepristone for Advanced, Glucocorticoid Receptor-Positive, Triple-Negative Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Mifepristone; Placebo; Nab-Paclitaxel
Intervention description: Patients will receive mifepristone 300 mg daily on the day prior to and day of each dose of nab-paclitaxel (100 mg/m2 on days 1, 8 and 15 of each 28 day cycle).; Patients will receive placebo and nab-paclitaxel (100 mg/m2 on days 1, 8 and 15 of each 28 day cycle).; Patients will either receive placebo and nab-paclitaxel (100 mg/m2 on days 1, 8 and 15 of each 28 day cycle) or patients will receive mifepristone 300 mg daily on the day prior to and day of each dose of nab-paclitaxel (100 mg/m2 on days 1, 8 and 15 of each 28 day cycle). Patients will receive mifepristone and nab-paclitaxel, or placebo and nab-paclitaxel. Not all three.
Intervention MeSH terms: Paclitaxel; Mifepristone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: triple-negative breast cancer; advanced breast cancer; nab-paclitaxel; mifepristone; glucocorticoid receptor-positive breast cancer

Summary:

      This is a randomized, placebo-controlled, double-blind, phase II trial of nab-paclitaxel with
      or without mifepristone for advanced, glucocorticoid receptor-positive, triple-negative
      breast cancer. A total of 64 patients will receive nab-paclitaxel. Patients will be randomly
      assigned to either receive placebo or to receive mifepristone daily on the day prior to and
      day of each dose of nab-paclitaxel. Patients will be enrolled over 12 months and followed for
      12 months following completion of study.

      To expand and follow up on the investigators understanding of a potential pharmacokinetic
      (PK) interaction between nab-paclitaxel and mifepristone, investigators will perform PK
      studies in the first 20 patients enrolled at pre-specified "PK sites".
    

Eligibility criteria:

        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.