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

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

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of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial.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.

Study Overview

• Status: Unknown
• Conditions: Primary Breast Cancer ER+ve; Primary Breast Cancer AR+ve TNBN
• Intervention / Treatment: Drug: Enzalutamide; Drug: Exemestane

• Study Type: Interventional
• Enrollment (Actual): 221
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bergisch Gladbach, Germany, 51465
    • Evangelisches Krankenhaus Bergisch Gladbachg GmbH Frauenklinik
  • Berlin, Germany, 10117
    • Charité Campus Mitte
  • Berlin, Germany, 13589
    • Evangelisches Waldkrankenhaus Spandau
  • Berlin, Germany, 10713
    • Brustzentrum City St. Gertraudenkrankenhaus
  • Berlin Köpenick, Germany, 12559
    • DRK Kliniken Berlin Köpenick
  • Bonn, Germany, 53113
    • Johanniter Krankenhaus Bonn
  • Bremen, Germany, 28209
    • Onkologische Schwerpunktpraxis Bremen
  • Chemnitz, Germany, 09116
    • Klinikum Chemnitz GmbH
  • Essen, Germany, 45136
    • Kliniken-Essen-Mitte, Senology
  • Frankfurt, Germany, 60431
    • Agaplesion Markus Krankenhaus
  • Gelsenkirchen, Germany, 45879
    • Evangelische Kliniken Gelsenkirchen
  • Hannöver, Germany, 30559
    • Hannover Diakovere Henriettenstift
  • Kassel, Germany, 34125
    • Klinikum Kassel
  • Kempten, Germany, 87439
    • Klinikum Kempten
  • Kiel, Germany, 24105
    • UKSH -Campus Kiel
  • Köln, Germany, 50931
    • Brustzentrum Uniklinik Köln
  • Köln, Germany, 50935
    • St. Elisabeth Krankenhaus Köln
  • Köln, Germany, 51067
    • Brustzentrum Holweide
  • Lübeck, Germany, 23538
    • UKSH Lübeck
  • Lüneburg, Germany, 21339
    • UKSH Lüneburg, Städtisches Krankenhaus
  • Minden, Germany, 32429
    • Johannes wesling Klinikum (Minden Hospital)
  • Monchengladbach, Germany, 41061
    • Brustzentrum Niederrhein / ÜBAG Prof. Nitz Mönchengladbach
  • München, Germany, 80637
    • Onkologisches Zentrum am Rotkreuzklinikum München
  • Schwerin, Germany, 19049
    • Helios-Kliniken Schwerin
  • Stendal, Germany, 39576
    • Johanniter Frauenklinik Stendal
  • Troisdorf, Germany, D-53840
    • Praxisnetzwerk Trosidorf
  • Weinheim, Germany, 69469
    • GRN Klinik Weinheim
  • Witten, Germany, 58452
    • Marienhospital Witten
• Ireland
  • Belfast, Ireland, BT9 7AB
    • Belfast Health and Social Care Trust
• Spain
  • Barcelona, Spain, 08035
    • Vall Hebron Hospital
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital and Medical School NHS Tayside
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter NHS Foundation Trust
  • London, United Kingdom, SE19RT
    • Guy's and St Thomas' NHS Foundation Trust
  • London, United Kingdom, EC1M 6BQ
    • Barts Health NHS Trust
  • Manchester, United Kingdom, M239QZ
    • University Hospital of South Manchester
  • Manchester, United Kingdom, M8 5RB
    • North Manchester Hospital, Pennine Acute Hospitals NHS Trust
  • Oxford, United Kingdom, OX37LI
    • Churchill Hospital Oxford University Hospitals NHS Trust
  • Stockton-on-Tees, United Kingdom, TS19 8PE
    • University Hospital of North Tees
  • Surrey, United Kingdom, GU2 7XX
    • Royal Surrey County Hospital NHS Foundation Trust
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR13LJ
      • Royal Cornwall Hospitals NHS Trust
• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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; Anti-androgen; 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; Anti-androgen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the difference in geometric mean change in Ki67 expression between the two treatment groups of patients in the ER+ Cohort	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	24 months
Determine the individual anti-proliferative response (RRΔKi67) for patients in the AR+ TNBC cohort	The anti-proliferative response is defined as a ≥50% fall in Ki67 expression over the course of the study treatment	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the geometric mean change in Ki67 expression at the end of study treatment (Mean ΔKi67) for patients in the AR+ TNBC cohort		24 months
Determine the geometric mean Ki67 expression at the end of study treatment (Mean Ki67post) for patients in the ER+ cohort		24 months
Determine the individual end-of treatment anti-proliferative response (RRKi67-Post) for all patients.	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.	24 months
Determine the individual anti-proliferative response (RRΔKi67) for patients in the ER+ cohort.	The RRΔKi67 is defined as a ≥50% fall in Ki67 expression over the course of the study treatment	24 months
Determine the geometric mean change in Caspase-3 between end of study treatment and pre-treatment tumour samples (Mean ΔCaspase-3).		24 months
Determine the individual apoptotic response (RRΔCaspase-3).	RRΔCaspase-3 is defined as a ≥50% increase in Caspase-3 over the course of the study treatment	24 months
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	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	24 months
Measure the plasma levels of circulating hormones in blood samples collected prior to and at the end of study treatment.	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.	24 months

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Anticipated): March 1, 2020
• Study Completion (Anticipated): March 1, 2020

Study Registration Dates

• First Submitted: February 1, 2016
• First Submitted That Met QC Criteria: February 3, 2016
• First Posted (Estimate): February 9, 2016

Study Record Updates

• Last Update Posted (Actual): February 25, 2020
• Last Update Submitted That Met QC Criteria: February 24, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: TNBC; Primary Breast Cancer; ER; AR
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Exemestane
• Other Study ID Numbers: 009684QM; 2014-002001-37 (EudraCT Number)