PIONEER

Overview

Pioneer is a three arm, open-label, multi-centre, randomized, window-of-opportunity, phase II trial which will evaluate the effects of 15 days (+ £4 days) preoperative therapy with Letrozole plus Megestrol acetate (40mg or 160mg), compared to letrozole alone in postmenopausal women with newly diagnosed, ER-positive, HER2-negative, invasive primary breast cancer of at least 1 cm size.

Recent preclinical findings have been published which provide new insights into the functional ‘cross-talk’ between the oestrogen receptor (ER) and progesterone receptor (PR) in breast cancer. Addition of a PR agonist to anti-oestrogens directly modifies ERa chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro and in vivo.

Megestrol Acetate is an off-patent semi-synthetic derivative of progesterone and has been licensed for many years as a treatment for ER+ metastatic breast cancer (at 160mg daily). There is also good evidence for efficacy of megestrol acetate at lower doses (20-40mg daily) as a supportive therapy to ameliorate endocrine therapy-related hot flushes.

Objectives

Primary

• To determine if the addition of Megestrol Acetate increases the anti-proliferative effect of Letrozole when given for 15 days pre-operatively in patients with early-stage, ER-positive breast cancer, as measured by change in Ki67.

Secondary

• To compare and correlate the biological effects of Letrozole alone compared to Letrozole plus Megestrol Acetate using other immunohistochemical markers of tumour response: Caspase 3, Aurora kinase A, change in expression of the androgen and progesterone receptors, and the absolute value of Ki67 at Day 15
• To compare and correlate the change in Ki67 and the biological effects of low dose Megestrol Acetate compared to high dose Megestrol Acetate using other immunohistochemical markers of tumour response: Caspase 3, Aurora kinase A, change in expression of the androgen and progesterone receptors, and the absolute value of Ki67 at Day 15
• To assess the safety and tolerability of the combination of Letrozole +/- Megestrol Acetate by recording and assessing adverse and serious adverse events.

Inclusion criteria

• Histologically confirmed breast adenocarcinoma
• Postmenopausal women
• Core biopsy confirmation of invasive carcinoma on core biopsy, ≥T1c, either clinically NX or N0-N3
• ER positive (Allred≥3) and HER2 negative
• 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 109/L and Plt count ≥100 x 109/L

• Written informed consent (IC) to participate in the trial and to donation of tissue.

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 tumour excision 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 tumour excision or as neoadjuvant therapy prior to tumour excision– such patients must begin PIONEER trial therapy prior to starting any other endocrine therapy.

Planned sample size

189 evaluable patients

Total number of sites planned

10-15 UK sites

Timeline

Completing recruitment: 31st March 2020

Extension until end of 2020 granted