Clinical Trials /

Short-term Preoperative Treatment With Enzalutamide, Alone or in Combination With Exemestane in Primary Breast Cancer



Open-label, international, multicentre window of opportunity phase II trial to evaluate the effects of short-term preoperative therapy with enzalutamide (alone or in combination with exemestane) in women with newly diagnosed invasive primary breast cancer. The study has two cohorts: - ER+ve breast cancer - AR+ve, Triple-negative (i.e. ER-negative, PR-negative and HER2-negative) breast cancer Study treatment is planned for a minimum of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial. Thereafter, patients will either be considered for definitive surgery or primary medical treatment (e.g. neoadjuvant chemotherapy) at the discretion of the treating physician. The effects of enzalutamide (alone or in combination with exemestane) will be assessed on tumour tissue specimens taken at baseline and on the last day of study treatment.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting


Phase 2

Trial Eligibility


Phase II Window of Opportunity Study of Short-term Preoperative Treatment With <span class="go-doc-concept go-doc-intervention">Enzalutamide</span> (Alone or in Combination With <span class="go-doc-concept go-doc-intervention">Exemestane</span>) in Patients With Primary Breast Cancer


  • Brief Title: Phase II Window of Opportunity Study of Short-term Preoperative Treatment With Enzalutamide (Alone or in Combination With Exemestane) in Patients With Primary Breast Cancer
  • Official Title: Phase II Window of Opportunity Study of Short-term Preoperative Treatment With Enzalutamide (Alone or in Combination With Exemestane) in Patients With Primary Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02676986


    Trial Conditions

    Primary Breast Cancer ER+ve

    Primary Breast Cancer AR+ve TNBN

    Trial Interventions

    Drug Synonyms Arms
    Enzalutamide Cohort I (ER positive cohort), Cohort II (AR positive, TNBC cohort)
    Exemestane Cohort I (ER positive cohort)

    Trial Purpose

    This study is being carried out to see if the antiandrogen enzalutamide has antitumour
    effects in early breast cancer.

    Enzalutamide blocks the action of androgens on the androgen receptor (AR) and may slow down
    or stop breast cancers growing. Enzalutamide is approved for the treatment of prostate

    The trial will be offered to patients who have just been diagnosed with early breast cancer
    and who are planned to have surgery in the next few weeks. The treatment will bridge the
    time between the diagnosis and surgery and will be given for 2- 4 weeks. To assess the
    effect of the treatment, small samples of breast cancer tissue will be analysed before the
    start and after treatment. The pre-treatment assessment will be done on archived tissue but
    patients might require an additional biopsy, if sufficient stored tumour tissue is not
    available. The end of treatment samples will be taken during surgery, unless the patient
    will receive medical treatment first instead of surgery which might mean additional biopsies
    of the breast cancer have to be taken. The trial has two cohorts. The cohort of patients
    with oestrogen receptor (ER) positive breast cancer will test if adding enzalutamide to
    exemestane is better at slowing the growth of breast cancer than exemestane alone. This
    cohort will recruit 141 evaluable post-menopausal patients with a tumour size of at least 1
    cm. The aromatase inhibitor exemestane is approved for the treatment of ER positive breast
    cancer. Blocking aromatase decreases oestrogens but can increase androgens. Enzalutamide is
    therefore added to block the action of androgens on the AR.

    In the second cohort of patients with triple negative breast cancer (TNBC), enzalutamide
    will be given alone to see if it can slow the growth tumours with androgen receptors. As
    only approximately 30% of TNBCs express the AR, a pre screening step will be included to
    test the tumour AR expression, before patients are approached for the ARB trial. The TNBC
    cohort will comprise 55 patients.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Cohort I (ER positive cohort) Active Comparator Approximately 180 patients with ER positive breast cancer will be randomised 2:1 in favour of enzalutamide to receive enzalutamide plus exemestane or exemestane alone. Enzalutamide, Exemestane
    Cohort II (AR positive, TNBC cohort) Active Comparator 55 patients with AR positive, TNBC will receive single agent treatment with enzalutamide. Enzalutamide

    Eligibility Criteria

    Main Inclusion Criteria:

    1. Written informed consent prior to admission to this study

    2. Female, aged 18 years

    3. ECOG performance status 0- 2

    4. Histologically confirmed invasive primary breast cancer

    5. Palpable breast tumour of any size, or tumour with an ultrasound or MRI size of at
    least 1.0 cm

    6. Haematologic and biochemical indices within the ranges shown below at the screening

    1. ANC 1500 cells/l

    2. Platelet count 100000/l

    3. Serum creatinine concentration < 1.5 x ULN

    4. Bilirubin level < 1.5 x ULN

    5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN

    Inclusion Criteria unique to the ER+ve cohort:

    1. ER+ve tumours defined as 1% of tumour cells positive for ER on IHC staining or an
    IHC score (Allred) of 3

    2. Postmenopausal defined as:

    1. Age 55 years and 1 year or more of amenorrhea

    2. Age 55 years and 1 year or more of amenorrhea with LH and/or FSH levels in the
    postmenopausal range

    3. Age 55 with prior hysterectomy but intact ovaries with LH and/or FSH levels in
    the postmenopausal range

    4. Status after bilateral oophorectomy ( 28 days prior to first study treatment)

    Inclusion Criteria unique to the AR+ve, TNBC cohort:

    1. AR positive tumours defined as any nuclear AR staining by IHC (enrolment may be based
    on local pathology findings; subsequent review of AR expression by central pathology
    laboratory will be carried out)

    2. Triple-negative tumours, i.e. tumour cells are negative for

    1. ER with <1% of cells positive on IHC or an IHC score (Allred) of 2

    2. PR with <1% of tumour cells positive on IHC or an Allred score of 2

    3. HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the
    HER2 gene on ISH

    3. Negative serum or urine pregnancy test for women of childbearing potential within 2
    weeks prior to the first dose of study treatment, preferably as close to the first
    dose as possible. Patients of childbearing potential must agree to use adequate
    contraception (for example, intrauterine device [IUD], birth control pills unless
    clinically contraindicated, or barrier device) beginning 2 weeks before the first
    dose of investigational medicinal product (IMP) and for 30 days after the final dose
    of IMP.

    Exclusion Criteria:

    1. Inflammatory breast cancer

    2. Treatment with any of the following medications within 4 weeks before the baseline
    diagnostic biopsy is taken:

    1. Oestrogens, including hormone replacement therapy;

    2. Androgens (testosterone, dihydroepiandrosterone, etc.);

    3. Any approved or investigational agent that blocks androgen synthesis or targets
    the AR (e.g., abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201,
    TAK-448, TAK-683, TAK-700)

    3. Previous systemic or local treatment for the new primary breast cancer currently
    under investigation (including surgery, radiotherapy, cytotoxic and endocrine
    treatments); prior treatment for previous breast cancer or other neoplasms is allowed
    as long as it was completed at least 1 year prior to inclusion into this trial.

    4. History of seizure or any condition that may predispose to seizure; history of loss
    of consciousness or transient ischemic attack within 12 months before day 1.

    5. Significant cardiovascular disease, such as

    1. History of myocardial infarction, acute coronary syndromes or coronary
    angioplasty/stenting/bypass grafting within the past 6 months.

    2. Congestive heart failure New York Heart Association (NYHA) Class III or IV or
    history of congestive heart failure NYHA class III or IV, unless an
    echocardiogram or multigated acquisition scan performed within 3 months before
    day 1 reveals a left ventricular ejection fraction 45%;

    3. History of clinically significant ventricular arrhythmias (e.g., ventricular
    tachycardia, ventricular fibrillation, torsade de pointes);

    6. Hypersensitivity to the active pharmaceutical ingredient or any of the excipients of
    the IMPs, including Labrasol, butylated hydroxyanisole, and butylated Hydroxytoluene

    7. Any other disease, metabolic dysfunction, physical examination finding, or clinical
    laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
    a disease or condition that contraindicates the use of an IMP, may affect the
    interpretation of the results, render the patient at high risk from treatment
    complications or interferes with obtaining informed consent.

    8. Psychological, familial, sociological or geographical conditions that do not permit
    compliance with the study protocol.

    9. Concurrent treatment with other experimental drugs. Participation in another clinical
    trial with any investigational drug within 4 weeks prior to study entry.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Determine the difference in geometric mean change in Ki67 expression between the two treatment groups of patients in the ER+ Cohort

    Determine the individual anti-proliferative response (RRKi67) for patients in the AR+ TNBC cohort

    Secondary Outcome Measures

    Determine the geometric mean change in Ki67 expression at the end of study treatment (Mean Ki67) for patients in the AR+ TNBC cohort

    Determine the geometric mean Ki67 expression at the end of study treatment (Mean Ki67post) for patients in the ER+ cohort

    Determine the individual end-of treatment anti-proliferative response (RRKi67-Post) for all patients.

    Determine the individual anti-proliferative response (RRKi67) for patients in the ER+ cohort.

    Determine the geometric mean change in Caspase-3 between end of study treatment and pre-treatment tumour samples (Mean Caspase-3).

    Determine the individual apoptotic response (RRCaspase-3).

    Establish the safety and tolerability of enzalutamide alone and in combination with exemestane in this population through review of all AEs and SAEs assessed by CTCAE v4.03

    Measure the plasma levels of circulating hormones in blood samples collected prior to and at the end of study treatment.

    Trial Keywords

    Primary Breast Cancer