A Pre-operative Window Study of Letrozole Plus PR Agonist (Megestrol Acetate) Versus Letrozole Alone in Post-menopausal Patients With ER-positive Breast Cancer (PIONEER)
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|ClinicalTrials.gov Identifier: NCT03306472|
Recruitment Status : Recruiting
First Posted : October 11, 2017
Last Update Posted : January 7, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Megestrol Acetate 40 MG Drug: Megestrol Acetate 160 MG Drug: Letrozole||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||189 participants|
|Intervention Model:||Parallel Assignment|
|Intervention 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)|
|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|
|Actual Study Start Date :||July 20, 2017|
|Estimated Primary Completion Date :||September 30, 2020|
|Estimated Study Completion Date :||December 30, 2021|
Active Comparator: Arm A: Letrozole
Arm A: 15 days of Letrozole 2.5mg daily
Experimental: Arm B: Letrozole + Megestrol Acetate (40mg)
Arm B: 15 days of Letrozole 2.5mg daily + Megestrol acetate 40mg daily
Drug: Megestrol Acetate 40 MG
Other Name: Megace
Experimental: Arm C: Letrozole + Megestrol Acetate (160mg)
Arm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily.
Drug: Megestrol Acetate 160 MG
Other Name: Megace
- 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.
- 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.
- 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
- 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
- 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.
- 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
- 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).
- 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.
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03306472
|Contact: Angels Kateb Castellnou||01223 348073 ext email@example.com|
|Contact: Louise Grybowicz||01223 348086 ext firstname.lastname@example.org|
|Cambridge University Hospitals NHS Foundation Trust||Recruiting|
|Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ|
|Contact: Angels Kateb Castellnou, BSc, MSc 01223 348073 email@example.com|
|Principal Investigator: Richard Baird, MA MBBS PhD FRCP|
|Principal Investigator:||Richard Baird, MA MBBS PhD FRCP||Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge|