Breast CancerPhase 2PIONEERNCT03306472
A Pre-operative Window Study of Letrozole Plus PR Agonist (Megestrol Acetate) Versus Letrozole Alone in Post-menopausal Patients With ER-positive Breast Cancer
A Phase 2 study testing Megestrol Acetate 40 MG, Megestrol Acetate 160 MG and Letrozole in people with Breast Cancer, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
Around 75% of breast cancers are defined and driven by Oestrogen receptor alpha (ERα) transcriptional activity. Standard treatment is endocrine therapy however clinical outcomes vary considerably, and a proportion of women with early breast cancer driven by ERα transcriptional activity develop drug resistance, and… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Megestrol Acetate 40 MG, Megestrol Acetate 160 MG and Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 198 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 20 Jul 2017to 31 Oct 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed breast adenocarcinoma
- Postmenopausal women
- Core biopsy confirmation of invasive carcinoma on core biopsy, ≥T1c, either clinical NX or N0-N3
- ER positive (Allred≥3) and HER2 negative
- 2 groups of patients are potentially eligible:
- Cohort A: Patients whose cancers have been deemed to be operable by the Multi-Disciplinary Team (MDT), with surgery planned for the next 2-6 weeks
Show all 13Show fewer
- Cohort B: Patients with early or locoregionally advanced breast cancer planned for primary endocrine therapy, either in lieu of surgery or as neoadjuvant therapy prior to surgery- such patients must begin PIONEER trial therapy prior to starting any other endocrine therapy.
- ECOG performance status of 0, 1 or 2
- Adequate Liver, Renal and Bone marrow function, defined as:
- Adequate liver function where bilirubin is ≤1.5 x ULN
- Adequate renal function with serum creatinine ≤ 1.5 x ULN
- Adequate bone marrow function with ANC ≥1.0 x 10*9/L and Platelet count ≥100 x 10*9/L
- Written informed consent to participate in the trial and to donation of tissue
Who cannot join
- History of hormone replacement therapy in the last 6 months
- Previous treatment with Tamoxifen or an aromatase inhibitor in the last six months
- Known hypersensitivity or contraindications to aromatase inhibitors or Megestrol acetate
- Known allergy to lactose
- Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation
- Known metastatic disease on presentation
Show all 11Show fewer
- Recurrent breast cancer (patients with a new primary invasive breast cancer will be eligible to participate)
- Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the trial, at the discretion of the investigator
- Treatment with an investigational drug within 4 weeks before randomisation
- Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication
- Inability to give informed consent
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Cambridge University Hospitals NHS Foundation Trust
Cambridge, Cambridgeshire, CB2 0QQ
About this study
Official 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
Around 75% of breast cancers are defined and driven by Oestrogen receptor alpha (ERα) transcriptional activity. Standard treatment is endocrine therapy however clinical outcomes vary considerably, and a proportion of women with early breast cancer driven by ERα transcriptional activity develop drug resistance, and relapse with incurable, metastatic disease.
Historically, PR-positivity was viewed as just a passive consequence of a functional oestrogen receptor, and PR was established as a biomarker of ER functionality in breast cancer. However, recent preclinical discoveries have provided an alternative explanation to the previous over-simplistic assumption, providing new insights into progestogen action and functional 'cross-talk' between ER and PR in breast cancer. In the presence of agonist ligands, progesterone-activated PR causes rapid sequestration of ERa chromatin binding sites in breast cancer cells, resulting in a unique gene expression program that is associated with a good clinical outcomes. This highlights a potential therapeutic opportunity.
The PIONEER trial will investigate the effect of combining megestrol acetate (a progesterone receptor agonist) and letrozole (an aromatase inhibitor) in post menopausal women with early breast cancer. This is a 'window of opportunity' study treating and observing patients in the two weeks prior to definitive surgery. Patients are randomised into one of three arms; one in which the patients receive Letrozole alone; one in which they will receive a combination of Letrozole and low dose Megestrol acetate and the third arm will receive Letrozole and high dose Megestrol acetate. This trial will be open to postmenopausal women with newly diagnosed, untreated ER-positive, HER2-negative, invasive primary breast cancer.
- Conditions
- Breast Cancer
- Being tested
- Megestrol Acetate 40 MG, Megestrol Acetate 160 MG, Letrozole
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Megestrol Acetate 40 MGDrug
Also called Megace
Progesterone Agonist
Megestrol Acetate 160 MGDrug
Also called Megace
Progesterone Agonist
LetrozoleDrug
Aromatase Inhibitor
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Letrozole | Active comparator | Arm A: 15 days of Letrozole 2.5mg daily Receives: Drug: Letrozole |
| Arm B: Letrozole + Megestrol Acetate (40mg) | Experimental | Arm B: 15 days of Letrozole 2.5mg daily + Megestrol acetate 40mg daily Receives: Drug: Megestrol Acetate 40 MG; Drug: Letrozole |
| Arm C: Letrozole + Megestrol Acetate (160mg) | Experimental | Arm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily. Receives: Drug: Megestrol Acetate 160 MG; Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of change in tumour proliferation measured by Ki67 immunohistochemical (IHC) assessment (%) at baseline compared to Day 15 (+ ≤4 days).
Tumour-cell Ki67 antigen labeling index will be recorded following the recommendations from the International Ki67 working group. Ki67 will be scored as the percentage of tumour nuclei staining. The investigators analyzing Ki67 will be blinded as to treatment allocation. Ki67-response is defined as a 50% or higher fall in Ki67 expression.
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Secondary outcomes (6)
Change in tumour apoptosis, measured by Caspase 3 (IHC)
Caspase-3 is activated by cleavage in cells undergoing apoptosis. Capase-3 IHC has been validated as a marker of apoptosis in breast cancer.
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in expression of Androgen receptor and Progesterone receptor by IHC
IHC of PR will be performed as a surrogate of ER activity. IHC of AR will be performed as AR influences ER-alpha activity in breast cancer, and has been shown to be a predictor of response to other synthetic progestins in breast cancer. Both PR and AR levels will be correlated with Ki67 changes
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in expression of Epithelial-Mesenchymal Transition (EMT) markers by IHC
IHC of epithelial markers E-Cadherin and Mesenchymal markers N-Cadherin, Fibronectin and Vimentin, to assess the effect of treatment on expression of genes validated to indicate risk of breast cancer progression and metastasis
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in proliferation by Aurora Kinase A labeling by IHC
Aurora Kinase A by IHC was found to outperform other proliferation markers as an independent predictor of breast cancer specific survival in ER-positive breast cancer, and will be analysed alongside Ki67.
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Absolute value of Ki67 at day 15 (+≤4 Days)
Measured to inform the development of a larger adjuvant trial following PIONEER. The absolute value of Ki67 at Day 15 has been found to be better predictive of recurrence free survival
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Incidence and Severity of Adverse Events
Determine the incidence and severity of adverse events caused by 15 days of treatment with letrozole (either alone or in combination with low or high dose megestrol acetate) prior to breast surgery. The severity of adverse events will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.03).
Measured: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2017
- Study start20 Jul 2017
- Primary completion31 Oct 2022
- Study completion31 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is a three arm, open-label, multicentre, randomized, window of opportunity, Phase II trial which will evaluate the effects of 15 days (+ 4 days) preoperative therapy with Letrozole, or Letrozole plus low dose Megestrol acetate (40mg), or Letrozole plus high dose Megestrol acetate (160mg) in postmenopausal women with newly diagnosed, ER-positive, HER2-negative, invasive primary breast cancer of at least 1 cm size.
- Masking
- None (open label)
- Enrolment
- 198 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cambridge University Hospitals NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Anticancer Fund, Belgium
- Responsible party
- Principal investigator, Richard D. Baird MD PhD, Cambridge University Hospitals NHS Foundation Trust
- Investigators
- Richard Baird, MA MBBS PhD FRCP, Principal investigator, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03306472
- Sponsor's protocol ID
- PIONEER
- Other IDs
- 2016-003752-79, 2016
- Acronym
- PIONEER
- Status last verified
- Jan 2024
- First submitted
- 26 May 2017
- Last updated
- 30 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Burrell RA, Kumar S, Provenzano E, Pike C, Dayimu A, McIntosh SA, Pitsinis V, King P, Elsberger B, Govindarajulu S, Satherley L, Hadad S, Schmid P, Agrawal A, Akpuluma B, Bell S, Benson JR, Caldas C, Cheeseman D, Chernukhin I, Forouhi P, Gulsen T, Kleidi E, Pinilla K, Qian W, Abraham JE, Carroll JS, Baird RD. Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial. Nat Cancer. 2026 Jan;7(1):194-206. doi: 10.1038/s43018-025-01087-x. Epub 2026 Jan 5.
PubMed 41492093
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT03306472
- Acronym / sponsor ID
- PIONEER / PIONEER
- Conditions
- Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 198 participants (actual)
- Lead sponsor
- Cambridge University Hospitals NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Anticancer Fund, Belgium
- Study start
- 20 Jul 2017 (actual)
- Primary completion
- 31 Oct 2022 (actual)
- Study completion
- 31 Oct 2023 (actual)
- First posted
- 11 Oct 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Around 75% of breast cancers are defined and driven by Oestrogen receptor alpha (ERα) transcriptional activity. Standard treatment is endocrine therapy however clinical outcomes vary considerably, and a proportion of women with early breast cancer driven by ERα transcriptional activity develop drug resistance, and relapse with incurable, metastatic disease.
Historically, PR-positivity was viewed as just a passive consequence of a functional oestrogen receptor, and PR was established as a biomarker of ER functionality in breast cancer. However, recent preclinical discoveries have provided an alternative explanation to the previous over-simplistic assumption, providing new insights into progestogen action and functional 'cross-talk' between ER and PR in breast cancer. In the presence of agonist ligands, progesterone-activated PR causes rapid sequestration of ERa chromatin binding sites in breast cancer cells, resulting in a unique gene expression program that is associated with a good clinical outcomes. This highlights a potential therapeutic opportunity.
The PIONEER trial will investigate the effect of combining megestrol acetate (a progesterone receptor agonist) and letrozole (an aromatase inhibitor) in post menopausal women with early breast cancer. This is a 'window of opportunity' study treating and observing patients in the two weeks prior to definitive surgery. Patients are randomised into one of three arms; one in which the patients receive Letrozole alone; one in which they will receive a combination of Letrozole and low dose Megestrol acetate and the third arm will receive Letrozole and high dose Megestrol acetate. This trial will be open to postmenopausal women with newly diagnosed, untreated ER-positive, HER2-negative, invasive primary breast cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- This is a three arm, open-label, multicentre, randomized, window of opportunity, Phase II trial which will evaluate the effects of 15 days (+ 4 days) preoperative therapy with Letrozole, or Letrozole plus low dose Megestrol acetate (40mg), or Letrozole plus high dose Megestrol acetate (160mg) in postmenopausal women with newly diagnosed, ER-positive, HER2-negative, invasive primary breast cancer of at least 1 cm size.
| Arm | Type | Receives |
|---|---|---|
| Arm A: Letrozole | Active comparator | Drug: LetrozoleArm A: 15 days of Letrozole 2.5mg daily |
| Arm B: Letrozole + Megestrol Acetate (40mg) | Experimental | Drug: Megestrol Acetate 40 MG, Drug: LetrozoleArm B: 15 days of Letrozole 2.5mg daily + Megestrol acetate 40mg daily |
| Arm C: Letrozole + Megestrol Acetate (160mg) | Experimental | Drug: Megestrol Acetate 160 MG, Drug: LetrozoleArm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Histologically confirmed breast adenocarcinoma
- Postmenopausal women
- Core biopsy confirmation of invasive carcinoma on core biopsy, ≥T1c, either clinical NX or N0-N3
- ER positive (Allred≥3) and HER2 negative
- 2 groups of patients are potentially eligible:
Key exclusion criteria (11 listed)
- History of hormone replacement therapy in the last 6 months
- Previous treatment with Tamoxifen or an aromatase inhibitor in the last six months
- Known hypersensitivity or contraindications to aromatase inhibitors or Megestrol acetate
- Known allergy to lactose
- Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Megestrol Acetate 40 MGAlso: MegaceProgesterone Agonist | Drug | Arm B: Letrozole + Megestrol Acetate (40mg) |
| Megestrol Acetate 160 MGAlso: MegaceProgesterone Agonist | Drug | Arm C: Letrozole + Megestrol Acetate (160mg) |
| LetrozoleAromatase Inhibitor | Drug | Arm A: Letrozole, Arm B: Letrozole + Megestrol Acetate (40mg), Arm C: Letrozole + Megestrol Acetate (160mg) |
Primary outcome
Determination of change in tumour proliferation measured by Ki67 immunohistochemical (IHC) assessment (%) at baseline compared to Day 15 (+ ≤4 days).
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Tumour-cell Ki67 antigen labeling index will be recorded following the recommendations from the International Ki67 working group. Ki67 will be scored as the percentage of tumour nuclei staining. The investigators analyzing Ki67 will be blinded as to treatment allocation. Ki67-response is defined as a 50% or higher fall in Ki67 expression.
6 secondary outcomes
Change in tumour apoptosis, measured by Caspase 3 (IHC)
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in expression of Androgen receptor and Progesterone receptor by IHC
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in expression of Epithelial-Mesenchymal Transition (EMT) markers by IHC
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Change in proliferation by Aurora Kinase A labeling by IHC
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Absolute value of Ki67 at day 15 (+≤4 Days)
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Incidence and Severity of Adverse Events
Time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2024.
- Derived from this study: PubMed 41492093Burrell RA, Kumar S, Provenzano E, Pike C, Dayimu A, McIntosh SA, Pitsinis V, King P, Elsberger B, Govindarajulu S, Satherley L, Hadad S, Schmid P, Agrawal A, Akpuluma B, Bell S, Benson JR, Caldas C, Cheeseman D, Chernukhin I, Forouhi P, Gulsen T, Kleidi E, Pinilla K, Qian W, Abraham JE, Carroll JS, Baird RD. Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial. Nat Cancer. 2026 Jan;7(1):194-206. doi: 10.1038/s43018-025-01087-x. Epub 2026 Jan 5.
- Individual participant dataSharing planned: No
Related trials for Breast Cancer
Not yet recruiting
Effect of a Health Belief Model Based Digital Nudge Intervention on Breast Cancer Screening
Breast Cancer Screening, Breast Cancer Awareness
Active, not recruitingPhase 1/2
A Beta-only IL-2 ImmunoTherapY Study
Advanced Solid Tumor, Unresectable Solid Tumor
Not yet recruitingPhase 2
Low-Dose Apatinib Plus Chemotherapy in ADC-Pretreated HER2-Positive and HER2-Low Advanced Breast Cancer
Breast Neoplasms, Advanced Breast Cancer
RecruitingPhase 3
ROSETTA Breast-01: The Effects and Safety of Pumitamig in Patients With Triple-Negative Breast Cancer
Breast Neoplasms
Active, not recruitingPhase 2
Phase II Study of Dato-DXd in Triple-negative Breast Cancer Patients With Newly Diagnosed or Progressing Brain Metastases
Breast Cancer Stage IV
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard Baird, MA MBBS PhD FRCP principal investigator
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Megestrol Acetate 40 MG, Megestrol Acetate 160 MG and Letrozole in people with Breast Cancer, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of change in tumour proliferation measured by Ki67 immunohistochemical (IHC) assessment (%) at baseline compared to Day 15 (+ ≤4 days). (time frame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03306472, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2024.