Clinical Trials /

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

NCT02676986

Description:

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of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial.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

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 009684QM
  • SECONDARY ID: 2014-002001-37
  • NCT ID: NCT02676986

Conditions

  • Primary Breast Cancer ER+ve
  • Primary Breast Cancer AR+ve TNBN

Interventions

DrugSynonymsArms
EnzalutamideCohort I (ER positive cohort)
ExemestaneCohort I (ER positive cohort)

Purpose

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of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial.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

Trial Arms

NameTypeDescriptionInterventions
Cohort I (ER positive cohort)Active ComparatorApproximately 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 Comparator55 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
             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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Queen Mary University of London

Trial Keywords

  • Primary Breast Cancer
  • ER
  • AR
  • TNBC

Last Updated

February 25, 2020