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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

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PIONEER
  • SECONDARY ID: 2016-003752-79
  • NCT ID: NCT03306472

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Megestrol Acetate 40 MGMegaceArm B: Letrozole + Megestrol Acetate (40mg)
Megestrol Acetate 160 MGMegaceArm C: Letrozole + Megestrol Acetate (160mg)
LetrozoleArm A: Letrozole

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A: LetrozoleActive ComparatorArm A: 15 days of Letrozole 2.5mg daily
  • Letrozole
Arm B: Letrozole + Megestrol Acetate (40mg)ExperimentalArm B: 15 days of Letrozole 2.5mg daily + Megestrol acetate 40mg daily
  • Megestrol Acetate 40 MG
  • Letrozole
Arm C: Letrozole + Megestrol Acetate (160mg)ExperimentalArm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily.
  • Megestrol Acetate 160 MG
  • Letrozole

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed breast adenocarcinoma

          -  Postmenopausal women

          -  Core biopsy confirmation of ER-positive (Allred>3), HER2-negative invasive carcinoma,
             ≥T1c, cN0 or N+ (TNM staging)

          -  Patients whose cancers have been deemed to be operable by the MDT

          -  Surgery is planned for the next 2-6 weeks

          -  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 estimated creatinine clearance of ≥60 ml/min

               -  Adequate bone marrow function with ANC ≥1.0 x 109/L and Platelet count ≥100 x
                  109/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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

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)
Safety Issue:
Description: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 Outcome Measures

Measure: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)
Safety Issue:
Description:Caspase-3 is activated by cleavage in cells undergoing apoptosis. Capase-3 IHC has been validated as a marker of apoptosis in breast cancer.
Measure: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)
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cambridge University Hospitals NHS Foundation Trust

Last Updated

October 5, 2017