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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 (PIONEER)

Primary Purpose

Breast Cancer

Status

Unknown status

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Megestrol Acetate 40 MG

Megestrol Acetate 160 MG

Letrozole

About this trial

This is an interventional treatment trial for Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Cambridge University Hospitals NHS Foundation TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Arm A: Letrozole

Arm B: Letrozole + Megestrol Acetate (40mg)

Arm C: Letrozole + Megestrol Acetate (160mg)

Arm Description

Arm A: 15 days of Letrozole 2.5mg daily

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

Arm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Change in tumour apoptosis, measured by Caspase 3 (IHC)

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

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

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

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)

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

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).

Full Information

NCT ID

NCT03306472

First Posted

May 26, 2017

Last Updated

January 12, 2021

Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

Anticancer Fund, Belgium

1. Study Identification

Unique Protocol Identification Number

NCT03306472

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

Acronym

PIONEER

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

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Unknown status

Study Start Date

July 20, 2017 (Actual)

Primary Completion Date

October 31, 2021 (Anticipated)

Study Completion Date

November 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

Anticancer Fund, Belgium

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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)

Masking Description

Unblinded

Allocation

Randomized

Enrollment

189 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A: Letrozole

Arm Type

Active Comparator

Arm Description

Arm A: 15 days of Letrozole 2.5mg daily

Arm Title

Arm B: Letrozole + Megestrol Acetate (40mg)

Arm Type

Experimental

Arm Description

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

Arm Title

Arm C: Letrozole + Megestrol Acetate (160mg)

Arm Type

Experimental

Arm Description

Arm C: 15 days of Letrozole 2.5mg daily + Megestrol acetate 160mg daily.

Intervention Type

Drug

Intervention Name(s)

Megestrol Acetate 40 MG

Other Intervention Name(s)

Megace

Intervention Description

Progesterone Agonist

Intervention Type

Drug

Intervention Name(s)

Megestrol Acetate 160 MG

Other Intervention Name(s)

Megace

Intervention Description

Progesterone Agonist

Intervention Type

Drug

Intervention Name(s)

Letrozole

Intervention Description

Aromatase Inhibitor

Primary Outcome Measure Information:

Title

Determination of change in tumour proliferation measured by Ki67 immunohistochemical (IHC) assessment (%) at baseline compared to Day 15 (+ ≤4 days).

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

Change in tumour apoptosis, measured by Caspase 3 (IHC)

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.

Time Frame

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

Title

Change in expression of Androgen receptor and Progesterone receptor by IHC

Description

Time Frame

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

Title

Change in expression of Epithelial-Mesenchymal Transition (EMT) markers by IHC

Description

Time Frame

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

Title

Change in proliferation by Aurora Kinase A labeling by IHC

Description

Time Frame

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

Title

Absolute value of Ki67 at day 15 (+≤4 Days)

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

Time Frame

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

Title

Incidence and Severity of Adverse Events

Description

Time Frame

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

Other Pre-specified Outcome Measures:

Title

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

Description

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

Time Frame

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

Title

Change in epithelial mesenchymal transition markers by IHC

Description

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.

Time Frame

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

Title

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

Description

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.

Time Frame

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

10. Eligibility

Sex

Female

Gender Based

Yes

Gender Eligibility Description

Yes: Eligibility is based on gender. Patients must be genetically female.

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Angels Kateb Castellnou

Phone

01223 348073

Ext

348073

angels.kateb@addenbrookes.nhs.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Louise Grybowicz

Phone

01223 348086

Ext

348086

louise.grybowicz@addenbrookes.nhs.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Richard Baird, MA MBBS PhD FRCP

Organizational Affiliation

Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cambridge University Hospitals NHS Foundation Trust

City

Cambridge

State/Province

Cambridgeshire

ZIP/Postal Code

CB2 0QQ

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Angels Kateb Castellnou, BSc, MSc

Phone

01223 348073

angels.kateb@addenbrookes.nhs.uk

pioneer@addenbrookes.nhs.uk

First Name & Middle Initial & Last Name & Degree

Richard Baird, MA MBBS PhD FRCP

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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