Breast Cancer - Anti-Progestin Prevention Study 1

Phase 1

Conditions: We seek to investigate the breast cancer risk reducing properties of ulipristal acetate
MedDRA version: 20.1Level: PTClassification code 10004746Term: Biopsy breast normalSystem Organ Class: 10022891 - Investigations
MedDRA version: 20.0Level: PTClassification code 10006187Term: Breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10071224Term: Breast scanSystem Organ Class: 10022891 - Investigations
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2015-001587-19-GB

Lead Sponsor: Manchester University NHS Foundation Trust

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Female

Target Recruitment: 30

Inclusion Criteria

Premenopausal females aged between 25 and 45 years
Regular menses defined as date of onset of last menstrual period +/- 3 days of expected
Known BRCA1 or BRCA2 mutation or moderate to high risk of developing BC defined as >17% lifetime risk from age 20 or >3% risk between 40-50 years
Ovulatory menstrual cycles defined as serum progesterone =15nmol 7 days prior to expected onset of menses.
eGFR = 40mls/min/1.73m2 in view of requirement for gadolinium contrast MRI scans
Willing and able to provide informed consent to undergo all trial procedures.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion Criteria

Personal history of breast, uterine, cervical or ovarian cancer

Breast feeding within the last 3 months

Pregnant or planning for pregnancy in the next 6 months. Pregnancy must be excluded with serum ßhCG <5nmol during screening.

Known hypersensitivity to radiological contrast media or to ulipristal acetate or any of its excipients (microcrystalline cellulose, mannitol, croscarmellose sodium, talc, magnesium stearate)

Current treatment with:

Anti-estrogens (e.g. tamoxifen or raloxifene), GnRH analogue therapy (e.g. goserelin or buserelin) or hormonal contraceptives including androgens such as cyproterone acetate. Such treatments must have been stopped for at least 6 months and regular menstrual cycles resumed.

Corticosteroids at any dose, these must have been stopped for at least 1 month with low likelihood that retreatment will be required

Antiplatelet or anticoagulant therapy – must have been stopped for at least 7 days and clotting be at satisfactory levels (see below)

moderate or potent inhibitors of CYP3A4 (for list see appendix)

potent inducers of CYP3A4 (for full list see appendix 1)

APTT and PT outside the normal institutional ranges. Hb <100g/l and platelet count <150x109/l. Serum creatinine, bilirubin, ALT, ALP or LDH >1,5xULN.

Contraindications to MRI, such as intracranial aneurysm clips, implanted electrical devices and intra-ocular metallic foreign bodies.

Co-morbidity that would put the patient at increased risk such as recognised bleeding diathesis, moderate to severe hepatic impairment, moderate or severe renal impairment (eGFR <40 ml/min/1.73m2), severe asthma not adequately controlled with corticosteroids (note steroid usage precludes trial entry)

Prior breast enhancement/augmentation surgery

Genital bleeding of unknown aetiology

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine whether three months of treatment with the antiprogestin ulipristal acetate reduces proliferation in the normal breast tissue of women at moderate to high risk of developing breast cancer.;Secondary Objective: 1. To examine the breast tissue of women treated with ulipristal acetate to determine its effects on: gene and protein expression, tissue stiffness and collagen organisation and the proportion and type of stem cells.<br><br>2. To relate the molecular changes above with MRI imaging biomarkers <br><br>3. To determine the side effect profile of UA in this patient population<br>;Primary end point(s): The change in the proliferation of normal breast epithelium, assessed by Ki67, from baseline to 3 months on treatment with ulipristal acetate;Timepoint(s) of evaluation of this end point: Comparison between baseline (pre treatment) and after 3 months of therapy

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): The changes in expression of individual genes and key pathways induced by UA therapy<br>The change in tissue stiffness and collagen organisation induced by UA therapy,<br>The changes in key stem cell and PgR target proteins induced by UA therapy<br>The proportion and type of clonogenic cells in the breast following treatment with UA <br>MRI imaging biomarkers of anti-progestin (UA) activity<br>The side effect profile of UA in this patient population<br>;Timepoint(s) of evaluation of this end point: All biological enpoints will be assessed at the 3 month timepoint as this is when the second biopsy or prophylactic mastectomy will be performed.<br><br>Toxicity (side effect profile) will be assessed monthly on therapy and at one month post cessation of ulipristal acetate

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