Clinical trial NCT02676986: Short-term Preoperative Treatment With Enzalutamide, Alone or in Combination With Exemestane in 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Breast Cancer ER+ve
Primary Breast Cancer AR+ve TNBN
Keywords: Primary Breast Cancer
ER
AR
TNBC
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2016-02-09
Enrollment: 221
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial.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


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 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.

Primary outcomes:
measure: Determine the difference in geometric mean change in Ki67 expression between the two treatment groups of patients in the ER+ Cohort
timeFrame: 24 months
measure: Determine the individual anti-proliferative response (RRΔKi67) for patients in the AR+ TNBC cohort
timeFrame: 24 months
Secondary outcomes:
measure: Determine the geometric mean change in Ki67 expression at the end of study treatment (Mean ΔKi67) for patients in the AR+ TNBC cohort
timeFrame: 24 months
measure: Determine the geometric mean Ki67 expression at the end of study treatment (Mean Ki67post) for patients in the ER+ cohort
timeFrame: 24 months
measure: Determine the individual end-of treatment anti-proliferative response (RRKi67-Post) for all patients.
timeFrame: 24 months
measure: Determine the individual anti-proliferative response (RRΔKi67) for patients in the ER+ cohort.
timeFrame: 24 months
measure: Determine the geometric mean change in Caspase-3 between end of study treatment and pre-treatment tumour samples (Mean ΔCaspase-3).
timeFrame: 24 months
measure: Determine the individual apoptotic response (RRΔCaspase-3).
timeFrame: 24 months
measure: 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
timeFrame: 24 months
measure: Measure the plasma levels of circulating hormones in blood samples collected prior to and at the end of study treatment.
timeFrame: 24 months
Other outcomes:
Locations:
city: Houston
country: United States
facility: MD Anderson Cancer Centre
state: Texas
city: Bergisch Gladbach
country: Germany
facility: Evangelisches Krankenhaus Bergisch Gladbachg GmbH Frauenklinik
city: Berlin Köpenick
country: Germany
facility: DRK Kliniken Berlin Köpenick
city: Berlin
country: Germany
facility: Charité Campus Mitte
city: Berlin
country: Germany
facility: Brustzentrum City St. Gertraudenkrankenhaus
city: Berlin
country: Germany
facility: Evangelisches Waldkrankenhaus Spandau
city: Bonn
country: Germany
facility: Johanniter Krankenhaus Bonn
city: Bremen
country: Germany
facility: Onkologische Schwerpunktpraxis Bremen
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH
city: Essen
country: Germany
facility: Kliniken-Essen-Mitte, Senology
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
city: Gelsenkirchen
country: Germany
facility: Evangelische Kliniken Gelsenkirchen
city: Hannöver
country: Germany
facility: Hannover Diakovere Henriettenstift
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kempten
country: Germany
facility: Klinikum Kempten
city: Kiel
country: Germany
facility: UKSH -Campus Kiel
city: Köln
country: Germany
facility: Brustzentrum Uniklinik Köln
city: Köln
country: Germany
facility: St. Elisabeth Krankenhaus Köln
city: Köln
country: Germany
facility: Brustzentrum Holweide
city: Lübeck
country: Germany
facility: UKSH Lübeck
city: Lüneburg
country: Germany
facility: UKSH Lüneburg, Städtisches Krankenhaus
city: Minden
country: Germany
facility: Johannes wesling Klinikum (Minden Hospital)
city: Monchengladbach
country: Germany
facility: Brustzentrum Niederrhein / ÜBAG Prof. Nitz Mönchengladbach
city: München
country: Germany
facility: Onkologisches Zentrum am Rotkreuzklinikum München
city: Schwerin
country: Germany
facility: Helios-Kliniken Schwerin
city: Stendal
country: Germany
facility: Johanniter Frauenklinik Stendal
city: Troisdorf
country: Germany
facility: Praxisnetzwerk Trosidorf
city: Weinheim
country: Germany
facility: GRN Klinik Weinheim
city: Witten
country: Germany
facility: Marienhospital Witten
city: Belfast
country: Ireland
facility: Belfast Health and Social Care Trust
city: Barcelona
country: Spain
facility: Vall Hebron Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
state: Cornwall
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School NHS Tayside
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter NHS Foundation Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: University Hospital of South Manchester
city: Manchester
country: United Kingdom
facility: North Manchester Hospital, Pennine Acute Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital Oxford University Hospitals NHS Trust
city: Stockton-on-Tees
country: United Kingdom
facility: University Hospital of North Tees
city: Surrey
country: United Kingdom
facility: Royal Surrey County Hospital NHS Foundation Trust
Study officials:
affiliation: Queen Mary University of London
name: Peter Schmid
role: PRINCIPAL_INVESTIGATOR
References: