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

NCT ID: NCT03306472

Last Updated: 2024-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 198 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-20
• Study Completion Date: 2023-10-31

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Letrozole

Arm A: 15 days of Letrozole 2.5mg daily

Group Type: ACTIVE_COMPARATOR

Letrozole

Intervention Type: DRUG

Aromatase Inhibitor

Arm B: Letrozole + Megestrol Acetate (40mg)

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

Group Type: EXPERIMENTAL

Megestrol Acetate 40 MG

Intervention Type: DRUG

Progesterone Agonist

Letrozole

Intervention Type: DRUG

Aromatase Inhibitor

Arm C: Letrozole + Megestrol Acetate (160mg)

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

Group Type: EXPERIMENTAL

Megestrol Acetate 160 MG

Intervention Type: DRUG

Progesterone Agonist

Letrozole

Intervention Type: DRUG

Aromatase Inhibitor

Interventions

Megestrol Acetate 40 MG

Progesterone Agonist

Intervention Type: DRUG

Megestrol Acetate 160 MG

Progesterone Agonist

Intervention Type: DRUG

Letrozole

Aromatase Inhibitor

Intervention Type: DRUG

Other Intervention Names

Megace; Megace

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Anticancer Fund, Belgium

OTHER

Sponsor Role: collaborator

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Richard D. Baird MD PhD

Honorary Consultant in Medical Oncology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard Baird, MA MBBS PhD FRCP

Role: PRINCIPAL_INVESTIGATOR

Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge

Locations

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom

Countries

United Kingdom

Other Identifiers

2016-003752-79

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PIONEER

Identifier Type: -

Identifier Source: org_study_id