A pre-surgery trial looking at the effect of combining megestrol acetate with letrozole or letrozole alone for postmenopausal patients with early, oestrogen receptor positive breast cancer

ISRCTN	ISRCTN15621797
DOI	https://doi.org/10.1186/ISRCTN15621797
EudraCT/CTIS number	2016-003752-79
ClinicalTrials.gov number	NCT03306472
Secondary identifying numbers	33915

Submission date: 02/05/2017
Registration date: 26/05/2017
Last edited: 16/10/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-megestrol-acetate-and-letrozole-for-women-with-breast-cancer-pioneer

Contact information

Mr Angels Kateb
Public

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Phone	+44 (0)1233 348073
Email	Pioneer@addenbrookes.nhs.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment, Screening, Drug, Surgery
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
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
Study acronym	PIONEER
Study objectives	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(s)	Newcastle & North Tyneside 1 Research Ethics Committee, 24/05/2017, ref: 17/NE/0113
Health condition(s) or problem(s) studied	ER-positive breast cancer in post-menopausal patients
Intervention	Patients will be randomised to one of three study arms. Arm A: Participants receive oral letrozole (2.5 mg) 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 40 mg 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
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Letrozole, 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 study start date	14/02/2016
Completion date	30/11/2022

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Female
Target number of participants	Planned Sample Size: 189; UK Sample Size: 189
Key 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 10(9)/L and Platelet count ≥100 x 10(9)/L 8. Written informed consent to participate in the trial and to donation of tissue
Key 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 6 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
Date of first enrolment	01/07/2017
Date of final enrolment	31/10/2021

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Cambridge University Hospitals NHS Foundation Trust

Addenbrooke’s Hospital
Cambridge Biomedical Campus
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Sponsor information

Cambridge University Hospitals NHS Foundation Trust
Hospital/treatment centre

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
England
United Kingdom

Phone	+44 1223 348490
Email	r&denquiries@addenbrookes.nhs.uk
"ROR"	https://ror.org/04v54gj93

Funders

Funder type

Research organisation

Het Anti-Kankerfonds - Le Fonds Anti-Cancer

No information available

Results and Publications

Intention to publish date	30/11/2023
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
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 plan	The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Basic results		15/10/2024	16/10/2024	No	No

Additional files

ISRCTN15621797 PIONEER Basic results.pdf

Editorial Notes

16/10/2024: The basic results have been uploaded as an additional file.
01/02/2021: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast" to "ER-positive breast cancer in post-menopausal women" following a request from the NIHR.
20/10/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/12/2018 to 31/10/2021.
2. The overall end date was changed from 01/12/2019 to 30/11/2022.
3. The intention to publish date was changed from 31/12/2019 to 30/11/2023.
20/08/2020: The primary contact was changed.
16/01/2020: ClinicalTrials.gov number added.
16/01/2018: Cancer Help UK lay summary link added to plain English summary field.
16/10/2017: Internal review.
11/08/2017: Internal review.
06/06/2017: Internal review.