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NCT Number: NCT03306472

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.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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
  • 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

Exclusion criteria

  • 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

Treatment and study plan

Megestrol Acetate 40 MG

Drug

Progesterone Agonist

Other names: Megace

Megestrol Acetate 160 MG

Drug

Progesterone Agonist

Other names: Megace

letrozole

Drug

Aromatase Inhibitor

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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)

    Caspase-3 is activated by cleavage in cells undergoing apoptosis. Capase-3 IHC has been validated as a marker of apoptosis in breast cancer.

  2. 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)

    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

  3. 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)

    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

  4. 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)

    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.

  5. 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)

    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

  6. 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)

    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).

Other outcomes

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

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

    ChIP-seq will allow demonstration of the robust and predictable ERα binding to novel genomic loci, mediated by PR.

  2. Change in epithelial mesenchymal transition markers by IHC

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

    To address the question of whether the combination of letrozole and megestrol acetate affects the metastatic potential of ER-positive breast cancer, IHC will be performed to compare the pre- and post-treatment cytoplasmic expression of E-cadherin and N-cadherin.

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

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

    To delineate potential underlying germline, somatic and pharmacogenetic reasons for response/non-response to trial treatment.If available, whole genome sequencing data from patients consented and recruited to studies collecting this information may be referenced.

Sponsors and collaborators

Lead sponsor

Cambridge University Hospitals NHS Foundation Trust

Other

Collaborators

  • Anticancer Fund, Belgium

Registry information

Official study 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

Important dates

Study start
2017
Primary completion
2022
Study completion
2023
First posted
Oct 11, 2017
Registry last updated
Jan 30, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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