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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02676986
Recruitment Status : Active, not recruiting
First Posted : February 9, 2016
Last Update Posted : December 20, 2018
Astellas Pharma Inc
Information provided by (Responsible Party):
Queen Mary University of London

Brief Summary:

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 cancer.

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.

Condition or disease Intervention/treatment Phase
Primary Breast Cancer ER+ve Primary Breast Cancer AR+ve TNBN Drug: Enzalutamide Drug: Exemestane Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 221 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
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
Actual Study Start Date : August 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Cohort I (ER positive cohort)
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.
Drug: Enzalutamide

Drug: Exemestane
Hormonal therapy (Licenced)

Active Comparator: Cohort II (AR positive, TNBC cohort)
55 patients with AR positive, TNBC will receive single agent treatment with enzalutamide.
Drug: Enzalutamide

Primary Outcome Measures :
  1. Determine the difference in geometric mean change in Ki67 expression between the two treatment groups of patients in the ER+ Cohort [ Time Frame: 24 months ]
    The geometric mean change will be determined by the change in Ki67 expression in tumour biopsy samples collected at the End of Treatment to those collected at Pre-Treatment

  2. Determine the individual anti-proliferative response (RRΔKi67) for patients in the AR+ TNBC cohort [ Time Frame: 24 months ]
    The anti-proliferative response is defined as a ≥50% fall in Ki67 expression over the course of the study treatment

Secondary Outcome Measures :
  1. Determine the geometric mean change in Ki67 expression at the end of study treatment (Mean ΔKi67) for patients in the AR+ TNBC cohort [ Time Frame: 24 months ]
  2. Determine the geometric mean Ki67 expression at the end of study treatment (Mean Ki67post) for patients in the ER+ cohort [ Time Frame: 24 months ]
  3. Determine the individual end-of treatment anti-proliferative response (RRKi67-Post) for all patients. [ Time Frame: 24 months ]
    The RRKi67-Post is defined as the natural logarithm of percentage positive Ki67 of less than 1 at the end of study treatment. For patients in the TNBC cohort, the analysis will be limited to patients with pre-treatment Ln (%Ki67) ≥ 1.

  4. Determine the individual anti-proliferative response (RRΔKi67) for patients in the ER+ cohort. [ Time Frame: 24 months ]
    The RRΔKi67 is defined as a ≥50% fall in Ki67 expression over the course of the study treatment

  5. Determine the geometric mean change in Caspase-3 between end of study treatment and pre-treatment tumour samples (Mean ΔCaspase-3). [ Time Frame: 24 months ]
  6. Determine the individual apoptotic response (RRΔCaspase-3). [ Time Frame: 24 months ]
    RRΔCaspase-3 is defined as a ≥50% increase in Caspase-3 over the course of the study treatment

  7. 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 [ Time Frame: 24 months ]

    Safety and tolerability will be assessed through reviewing:

    • Incidence of serious adverse events (SAEs)
    • Incidence of grade 3 and 4 adverse events (AEs) (CTCAE, version 4.03)
    • Incidence of all AEs of all grades
    • Clinically significant changes in vital signs and clinical laboratory results during and following study drug administration

  8. Measure the plasma levels of circulating hormones in blood samples collected prior to and at the end of study treatment. [ Time Frame: 24 months ]
    Plasma levels of androstenedione, DHT, estradiol, estrone, estrone sulfate, follicle stimulating hormone, luteinizing hormone, progesterone, sex hormone binding globulin, and total/free testosterone will be measured.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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 visit

    1. ANC 1500 cells/μl
    2. Platelet count 100000/μl
    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02676986

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United States, Texas
MD Anderson Cancer Centre
Houston, Texas, United States, 77030
Evangelisches Krankenhaus Bergisch Gladbachg GmbH Frauenklinik
Bergisch Gladbach, Germany, 51465
DRK Kliniken Berlin Köpenick
Berlin Köpenick, Germany, 12559
Charité Campus Mitte
Berlin, Germany, 10117
Brustzentrum City St. Gertraudenkrankenhaus
Berlin, Germany, 10713
Evangelisches Waldkrankenhaus Spandau
Berlin, Germany, 13589
Johanniter Krankenhaus Bonn
Bonn, Germany, 53113
Onkologische Schwerpunktpraxis Bremen
Bremen, Germany, 28209
Klinikum Chemnitz GmbH
Chemnitz, Germany, 09116
Kliniken-Essen-Mitte, Senology
Essen, Germany, 45136
Agaplesion Markus Krankenhaus
Frankfurt, Germany, 60431
Evangelische Kliniken Gelsenkirchen
Gelsenkirchen, Germany, 45879
Hannover Diakovere Henriettenstift
Hannöver, Germany, 30559
Klinikum Kassel
Kassel, Germany, 34125
Klinikum Kempten
Kempten, Germany, 87439
UKSH -Campus Kiel
Kiel, Germany, 24105
Brustzentrum Uniklinik Köln
Köln, Germany, 50931
St. Elisabeth Krankenhaus Köln
Köln, Germany, 50935
Brustzentrum Holweide
Köln, Germany, 51067
UKSH Lübeck
Lübeck, Germany, 23538
UKSH Lüneburg, Städtisches Krankenhaus
Lüneburg, Germany, 21339
Johannes wesling Klinikum (Minden Hospital)
Minden, Germany, 32429
Brustzentrum Niederrhein / ÜBAG Prof. Nitz Mönchengladbach
Monchengladbach, Germany, 41061
Onkologisches Zentrum am Rotkreuzklinikum München
München, Germany, 80637
Helios-Kliniken Schwerin
Schwerin, Germany, 19049
Johanniter Frauenklinik Stendal
Stendal, Germany, 39576
Praxisnetzwerk Trosidorf
Troisdorf, Germany, D-53840
GRN Klinik Weinheim
Weinheim, Germany, 69469
Marienhospital Witten
Witten, Germany, 58452
Belfast Health and Social Care Trust
Belfast, Ireland, BT9 7AB
Vall Hebron Hospital
Barcelona, Spain, 08035
United Kingdom
Royal Cornwall Hospitals NHS Trust
Truro, Cornwall, United Kingdom, TR13LJ
Ninewells Hospital and Medical School NHS Tayside
Dundee, United Kingdom, DD1 9SY
Royal Devon and Exeter NHS Foundation Trust
Exeter, United Kingdom, EX2 5DW
Barts Health NHS Trust
London, United Kingdom, EC1M 6BQ
Guy's and St Thomas' NHS Foundation Trust
London, United Kingdom, SE19RT
University Hospital of South Manchester
Manchester, United Kingdom, M239QZ
North Manchester Hospital, Pennine Acute Hospitals NHS Trust
Manchester, United Kingdom, M8 5RB
Churchill Hospital Oxford University Hospitals NHS Trust
Oxford, United Kingdom, OX37LI
University Hospital of North Tees
Stockton-on-Tees, United Kingdom, TS19 8PE
Sponsors and Collaborators
Queen Mary University of London
Astellas Pharma Inc
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Principal Investigator: Peter Schmid Queen Mary University of London

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Responsible Party: Queen Mary University of London Identifier: NCT02676986     History of Changes
Other Study ID Numbers: ARB
First Posted: February 9, 2016    Key Record Dates
Last Update Posted: December 20, 2018
Last Verified: December 2018
Keywords provided by Queen Mary University of London:
Primary Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs