A Window of Opportunity Study of Pre-operative Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Breast Hormone Receptor Positive (HR+) Human Epidermal Receptor 2 Negative (HER2-) Breast Cancer. (WinPro)

A Window of Opportunity Study of Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Hormone Receptor-positive Breast Cancer.

A phase II randomised, open label study of pre-operative endocrine therapy with & without prometrium in postmenopausal women with early stage breast hormone receptor positive (HR+) human epidermal receptor 2 negative (HER2-) breast cancer.

Study Overview

• Status: Recruiting
• Conditions: Hormone Receptor Positive Tumor; Early-stage Breast Cancer
• Intervention / Treatment: Drug: Letrozole; Drug: Letrozole and Prometrium; Drug: Tamoxifen and Prometrium

Detailed Description

There is bidirectional interplay between the progesterone receptor (PR) and oestrogen receptor (ER) in human breast cancers. There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines. Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models.

This is a phase II multi-site, randomised, open-label, three-arm, study in 200 postmenopausal women with early-stage ER+, PR+, HER2-negative breast cancer. Eligible patients will be randomised (1:1:1) to receive 14 days of intervention with either letrozole 2.5mg PO daily (arm 1), letrozole 2.5mg + prometrium 300mg PO daily (arm 2) or tamoxifen 20mg + prometrium 300mg PO daily (arm 3), between diagnosis of breast cancer and definitive surgery.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert Kent; Phone Number: +61293555611; Email: SVHS.CancerResearch@svha.org.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • Recruiting
      • St Vincent's Hospital
      • Contact: Robert Kent; Phone Number: +61293555611; Email: SVHS.CancerResearch@svha.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed ER+ and PR+ breast cancer (defined as ≥10% positive staining cells)
2. Histologically confirmed HER2-negative breast cancer (defined as IHC 0-1 and/or FISH/CISH <2.2)
3. Tumour size ≥1 cm as measured by ultrasound and/or mammogram
4. Ability to understand all patient information and informed-consent documents, written informed consent to participate in the trial, and to avail tissue and blood samples for research
5. Aged 18 years or older

Exclusion Criteria:

1. Women currently on hormone therapies, including hormone replacement therapy and oral contraceptive pill
2. Locally advanced/inoperable and inflammatory breast cancer
3. Planned for a mastectomy (due to increased risk of venous thromboembolism)
4. Clinical evidence of metastatic disease
5. Patients treated with other preoperative systemic therapies
6. Nut allergy (prometrium contains peanut oil)
7. Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder
8. Women who are pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Letrozole; Letrozole 2.5mg PO daily for 14 days between diagnosis of breast cancer and definite surgery	Drug: Letrozole; PO daily for 14 days
Experimental: Letrozole and Prometrium; Letrozole 2.5mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery	Drug: Letrozole and Prometrium; PO daily for 14 days
Experimental: Tamoxifen and Prometrium; Tamoxifen 20mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery	Drug: Tamoxifen and Prometrium; PO daily for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric mean suppression of proliferation marker Ki67	The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline	After two weeks of intervention, compared with baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability: number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Safety and tolerability of combination therapy (NCI-CTCAE v4.0)	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Define a gene set as a predictive biomarker for a reduction in Ki67	Expression of gene signature will be tested in the pre- and post-intervention tissues using the Nanostring nCounter system	4 years
Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention	Immunohistochemistry of the pre and post intervention tissue samples	4 years
Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention	Immunohistochemistry of the pre and post intervention tissue samples	4 years

Collaborators and Investigators

• Sponsor: St Vincent's Hospital
• Investigators: Principal Investigator: Elgene Lim, MBBS FRACP PhD, Garvan Research Institute

Publications and helpful links

General Publications

• Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD, D'Santos C, Robinson JL, Silva G, Launchbury R, Perou CM, Stingl J, Caldas C, Tilley WD, Carroll JS. Progesterone receptor modulates ERalpha action in breast cancer. Nature. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8. Erratum In: Nature. 2015 Oct 1;526(7571):144. Serandour, Aurelien A A[Corrected to Serandour, Aurelien A].
• Lim E, Tarulli G, Portman N, Hickey TE, Tilley WD, Palmieri C. Pushing estrogen receptor around in breast cancer. Endocr Relat Cancer. 2016 Dec;23(12):T227-T241. doi: 10.1530/ERC-16-0427. Epub 2016 Oct 11.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2018
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: April 5, 2019
• First Posted (Actual): April 8, 2019

Study Record Updates

• Last Update Posted (Actual): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: progesterone; endocrine therapy; post-menopausal; early stage breast cancer; prometrium
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Progestins; Letrozole; Tamoxifen; Progesterone
• Other Study ID Numbers: ACTRN1261000928213

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No