Clinical trial 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Anticancer Fund, Belgium
First posted: 2017-10-11
Enrollment: 198
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Determination of change in tumour proliferation measured by Ki67 immunohistochemical (IHC) assessment (%) at baseline compared to Day 15 (+ ≤4 days).
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Secondary outcomes:
measure: Change in tumour apoptosis, measured by Caspase 3 (IHC)
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Change in expression of Androgen receptor and Progesterone receptor by IHC
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Change in expression of Epithelial-Mesenchymal Transition (EMT) markers by IHC
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Change in proliferation by Aurora Kinase A labeling by IHC
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Absolute value of Ki67 at day 15 (+≤4 Days)
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Incidence and Severity of Adverse Events
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Other outcomes:
measure: Chromatin Immunoprecipitation followed by high throughput DNA Sequencing (ChIP-seq) of ER, conducted to assess progestin-induced ER reprogramming
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Change in epithelial mesenchymal transition markers by IHC
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
measure: Correlate differences in response to treatments with breast cancer genomic profiling datasets
timeFrame: Over 15 days of treatment with letrozole (alone or in combination with high or low dose megestrol acetate)
Locations:
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
name: Richard Baird, MA MBBS PhD FRCP
role: PRINCIPAL_INVESTIGATOR
References: