A Pre-operative Window Study of Letrozole Plus PR Agonist (Megestrol Acetate) Versus Letrozole Alone in Post-menopausal Patients With ER-positive Breast Cancer

NCT03306472 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: PIONEER2016-003752-79
• Study Type: interventional
• Target: 198
• Locations: 1 country
• Sites: 1

Brief 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 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

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  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

  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

  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

  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)

  Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)

Other Outcomes (3)

• Chromatin Immunoprecipitation followed by high throughput DNA Sequencing (ChIP-seq) of ER, conducted to assess progestin-induced ER reprogramming

  Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)

• Change in epithelial mesenchymal transition markers by IHC

  Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)

• Correlate differences in response to treatments with breast cancer genomic profiling datasets

  Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)

Study Arms (3)

Arm A: Letrozole

ACTIVE COMPARATOR

Arm A: 15 days of Letrozole 2.5mg daily

Drug: Letrozole

Arm B: Letrozole + Megestrol Acetate (40mg)

EXPERIMENTAL

Arm B: 15 days of Letrozole 2.5mg daily + Megestrol acetate 40mg daily

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.

Drug: Megestrol Acetate 160 MG; Drug: Letrozole

Interventions

Megestrol Acetate 40 MG DRUG

Progesterone Agonist

Also known as: Megace

Arm B: Letrozole + Megestrol Acetate (40mg)

Megestrol Acetate 160 MG DRUG

Progesterone Agonist

Also known as: Megace

Arm C: Letrozole + Megestrol Acetate (160mg)

Letrozole DRUG

Aromatase Inhibitor

Arm A: Letrozole; Arm B: Letrozole + Megestrol Acetate (40mg); Arm C: Letrozole + Megestrol Acetate (160mg)

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Yes: Eligibility is based on gender. Patients must be genetically female.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• Anticancer Fund, Belgium: collaborator

Study Sites (1)

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 41492093 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Megestrol Acetate; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Megestrol; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Richard Baird, MA MBBS PhD FRCP

  Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Honorary Consultant in Medical Oncology

Model Details: 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.

Study Record Dates

• First Submitted: May 26, 2017
• First Posted: October 11, 2017
• Study Start: July 20, 2017
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2023
• Last Updated: January 30, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)