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
Overview
- Phase
- Phase 2
- Intervention
- Enzalutamide
- Conditions
- Primary Breast Cancer ER+ve
- Sponsor
- Queen Mary University of London
- Enrollment
- 221
- Locations
- 41
- Primary Endpoint
- Determine the difference in geometric mean change in Ki67 expression between the two treatment groups of patients in the ER+ Cohort
- Status
- Completed
- Last Updated
- last year
Overview
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of 15 days and a maximum of 29 days unless there is evidence of unacceptable toxicity or the patient requests to be withdrawn from the trial.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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent prior to admission to this study
- •Female, aged ≥18 years
- •ECOG performance status 0- 2
- •Histologically confirmed invasive primary breast cancer
- •Palpable breast tumour of any size, or tumour with an ultrasound or MRI size of at least 1.0 cm
- •Haematologic and biochemical indices within the ranges shown below at the screening visit
- •ANC 1500 cells/μl
- •Platelet count 100000/μl
- •Serum creatinine concentration \< 1.5 x ULN
- •Bilirubin level \< 1.5 x ULN
Exclusion Criteria
- •Inflammatory breast cancer
- •Treatment with any of the following medications within 4 weeks before the baseline diagnostic biopsy is taken:
- •Oestrogens, including hormone replacement therapy;
- •Androgens (testosterone, dihydroepiandrosterone, etc.);
- •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)
- •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.
- •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
- •Significant cardiovascular disease, such as
- •History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months.
- •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%;
Arms & Interventions
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.
Intervention: Enzalutamide
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.
Intervention: Exemestane
Cohort II (AR positive, TNBC cohort)
55 patients with AR positive, TNBC will receive single agent treatment with enzalutamide.
Intervention: Enzalutamide
Outcomes
Primary Outcomes
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
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 Outcomes
- Determine the individual end-of treatment anti-proliferative response (RRKi67-Post) for all patients.(24 months)
- Determine the individual apoptotic response (RRΔCaspase-3).(24 months)
- Measure the plasma levels of circulating hormones in blood samples collected prior to and at the end of study treatment.(24 months)
- 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 anti-proliferative response (RRΔKi67) for patients in the ER+ cohort.(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)
- 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(24 months)