Additional identifiers
EudraCT number
2016-003752-79
ClinicalTrials.gov number
NCT03306472
Protocol/serial number
33915
Study information
Scientific title
Randomised Phase II clinical trial PIONEER: A Pre-operative wIndOw study of letrozole plus PR agonist (Megestrol Acetate) versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer
Acronym
PIONEER
Study hypothesis
The aim of this study is to investigate the effect of combining Megestrol Acetate (a progesterone receptor activator) and Letrozole (an anti-oestrogen, and standard endocrine therapy for post-menopausal women), in patients with newly diagnosed, untreated, ER-positive, HER2-negative, invasive primary breast cancer.
Ethics approval
Newcastle & North Tyneside 1 Research Ethics Committee, 24/05/2017, ref: 17/NE/0113
Study design
Randomised; Interventional; Design type: Treatment, Screening, Drug, Surgery
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast
Intervention
Patients will be randomised to one of three study arms.
Arm A: Participants receive oral Letrozole (2.5mg) alone daily for 15 days (this may be extended up to 19 days to accommodate the surgery date).
Arm B: Participants receive oral Letrozole 2.5mg plus Megestrol Acetate 40mg daily for 15 days (this may be extended up to 19 days to accommodate the surgery date).
Arm C: Participants receive oral Letrozole 2.5mg plus Megestrol Acetate 160mg daily for 15 days (this may be extended up to 19 days to accommodate the surgery date).
Intervention type
Drug
Phase
Phase II
Drug names
1. Letrozole
2. Megestrol Acetate
Primary outcome measure
Change in tumour proliferation is measured using Ki67 immuno-histochemical (IHC) assessment between pre-treatment (baseline) and post-treatment tumour samples (Day 15).
Secondary outcome measures
1. Change in tumour apoptosis is measured using Caspase 3 IHC assessment between pre-treatment (baseline) and post-treatment tumour samples (Day 15)
2. Changes in the expression of Androgen Receptor (AR) and Progesterone Receptor (PR) are measured using IHC assessment between pre-treatment (baseline) and post-treatment tumour samples (Day 15)
3. Change in proliferation by Aurora Kinase A (IHC) between baseline and Day 15 (+≤4 Days)
4. Change in tumour proliferation is also measured using Aurora Kinase A IHC assessment between pre-treatment (baseline) and post-treatment tumour samples (Day 15).
5. The absolute value of the Ki67 IHC assessment post-treatment (Day 15) is also recorded.
6. Safety of the trial treatments is assessed based on the incidence of serious adverse events and adverse events of all grades throughout the trial, grading is assessed using CTCAE criteria.
Exploratory Outcomes:
1. Transcription factor mapping of the Oestrogen Receptor (ER) will be assessed using ChIP-sequencing
2. The differences in response to treatments within the METABRIC-defined subtypes of ER-positive breast cancer will be assessed
Overall trial start date
14/02/2016
Overall trial end date
01/12/2019
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Histologically confirmed breast adenocarcinoma
2. Postmenopausal women, defined as having experienced:
2.1. 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. ≥50 years, history of vasomotor symptoms) or
2.2. Six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or
2.3. Surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.
3. Core biopsy confirmation of ER positive (Allred≥3) and HER2 negative invasive carcinoma on core biopsy, >=T1c, either cN0 or N+
4. Patients whose cancers have been deemed to be operable by the MDT
5. Surgery planned within the next 2-6 weeks
6. ECOG performance status of 0, 1 or 2
7. Adequate Liver, Renal and Bone marrow function, defined as:
7.1. Adequate liver function where bilirubin is ≤1.5 x ULN
7.2. Adequate renal function with estimated creatinine clearance of ≥60 ml/min
7.3. Adequate bone marrow function with ANC ≥1.0 x 109/L and Platelet count ≥100 x 109/L
8. Written informed consent to participate in the trial and to donation of tissue
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
Planned Sample Size: 189; UK Sample Size: 189
Participant exclusion criteria
1. History of hormone replacement therapy in the last 6 months
2. Previous treatment with tamoxifen or an aromatase inhibitor in the last six months
3. Known hypersensitivity or contraindications to aromatase inhibitors or megestrol acetate
4. Known allergy to lactose
5. Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation
6. Known metastatic disease on presentation
7. Recurrent breast cancer (patients with a new primary invasive breast cancer will be eligible to participate)
8. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator
9. Treatment with an investigational drug within 4 weeks before randomization
10. Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication
11. Inability to give informed consent
Recruitment start date
01/07/2017
Recruitment end date
01/12/2018
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Cambridge University Hospitals NHS Foundation Trust
Addenbrooke’s Hospital
Cambridge Biomedical Campus
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Organisation
Cambridge University Hospitals NHS Foundation Trust
Sponsor details
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
+44 1223 348490
r&denquiries@addenbrookes.nhs.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Research organisation
Funder name
Het Anti-Kankerfonds - Le Fonds Anti-Cancer
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal, with intent to have published by December 2019. Interim presentation of results in 2018/9 at local and international oncology meetings.
IPD Sharing statement:
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.
Intention to publish date
31/12/2019
Participant level data
Other
Basic results (scientific)
Publication list