Nab-Paclitaxel with or without Mifepristone in Treating Patients with Glucocorticoid Receptor Positive Stage IV or Stage III Triple-Negative Breast Cancer That Cannot Be Removed by Surgery

Status: Active

Description

This randomized phase II trial studies how well paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) with or without mifepristone works in treating glucocorticoid receptor positive stage IV or stage III triple-negative breast cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Progesterone and glucocorticoid can cause the growth of tumor cells. Hormone therapy using mifepristone may fight breast cancer by lowering the amount of progesterone and glucocorticoid the body makes or by blocking the use of progesterone and glucocorticoid by the tumor cells. It is not yet known whether nab-paclitaxel is more effective with or without mifepristone in treating patients with breast cancer.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically or cytologically confirmed breast cancer with stage IV or unresectable stage III disease
  • 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 computed tomography (CT) scan, magnetic resonance imaging (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)
  • Triple-negative breast cancer (defined as estrogen receptor [ER] and progesterone receptor [PR] < 10% positive; HER2 0-1+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] ratio < 2.0)
  • 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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500 cells/mm^3
  • 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 metastases (mets) are present
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ULN or =< 5 x ULN if liver mets are present
  • Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • International normalized ratio (INR) =< 1.5
  • Females of child-bearing potential (defined as a sexually mature woman who (1) has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must: * Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis), or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product (IP) therapy (including dose interruptions), and while on study medication or for a longer period if required by local regulations following the last dose of IP; and * Have a negative serum pregnancy test (beta-human chorionic gonadotropin [hCG]) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy; this applies even if the subject practices true abstinence from heterosexual contact
  • 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 * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception)
  • Patients must have < grade 2 pre-existing peripheral neuropathy (per Common Terminology Criteria for Adverse Events [CTCAE])
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients who are receiving any other investigational agents
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Pregnant women are excluded from this study
  • Breastfeeding should be discontinued if the mother wishes to participate in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • No history of long-term use of corticosteroids or concurrent short term use of corticosteroids is allowed

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Active
Contact: Erica M. Stringer-Reasor
Email: esreasor@uabmc.edu

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Rita Nanda
Phone: 773-834-2756
Email: rnanda@medicine.bsd.uchicago.edu
Evanston
NorthShore University HealthSystem-Evanston Hospital
Status: Active
Contact: Poornima Saha
Phone: 847-570-2515
Email: psaha@northshore.org

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: In review
Contact: Elias Obeid
Phone: 215-728-2792
Email: elias.obeid@fccc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. 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.

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

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

TERTIARY OBJECTIVES:

I. To expand on our understanding of the interaction between nab-paclitaxel and mifepristone by performing pharmacokinetic (PK) studies in the first 20 patients enrolled at pre-specified PK sites.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive mifepristone orally (PO) daily on days 0, 1, 7, 8, 14, and 15 and paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO daily on days 0, 1, 7, 8, 14, and 15 and paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 12 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Rita Nanda

Trial IDs

Primary ID IRB16-0403
Secondary IDs NCI-2016-01838
Clinicaltrials.gov ID NCT02788981