Condition category
Cancer
Date applied
04/09/2017
Date assigned
07/09/2017
Last edited
07/06/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

www.lctu.org.uk

Contact information

Type

Public

Primary contact

Ms Helen Scott

ORCID ID

Contact details

Cancer Research UK Liverpool Cancer Trials Unit
Block C
Waterhouse Building
1-3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Additional identifiers

EudraCT number

2017-001521-41

ClinicalTrials.gov number

Protocol/serial number

35420

Study information

Scientific title

A window of opportunity study to assess the biological effects of progesterone in premenopausal ER-positive, PgR-positive early breast cancer

Acronym

PEARL

Study hypothesis

The aim of the study is to evaluate the effects of two-weeks preoperative therapy with micronised progesterone alongside tamoxifen in premenopausal women with ER-positive, PgR-positive early breast cancer.

Ethics approval

North West Greater Manchester South Research Ethics Committee, 17/NW/0460

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast

Intervention

Patients are randomised 1:1 to either Tamoxifen plus micronised progesterone (therapeutic arm) or Tamoxifen alone (control arm). All participants take 100mg of Tamoxifen orally on Day 1, followed by 20mg of Tamoxifen orally, once daily from Day 2 until their scheduled breast surgery. Patients on the therapeutic arm also take 300mg micronised progesterone (Utrogestan) orally, once daily from Day 1 until their scheduled breast surgery. Surgery is scheduled for Day 14-18, so patients will receive study treatment for 14-18 days.

Following surgery, patients return 28 days later and the following procedures will be carried out at this visit:
1. Haematology and biochemistry
2. Adverse event review and recording
3. Translational blood sample collection

Adverse events will be reported until 28 days post treatment.

Intervention type

Other

Phase

Phase II

Drug names

Primary outcome measure

Changes in tumour cell proliferation will be measured using the Ki67 proliferation index at baseline (Day 0) and at surgery (Day 14-18).

Secondary outcome measures

1. Changes in the pro-aptoptic marker cleaved caspase 3 are measured using tissue immunohistochemistry at baseline (Day 0) and at surgery (Day 14-18)*
2. Changes in ER, PgR, FoxA1, Cyclin D1, RANKL protein and mRNA expression are measured using tissue immunohistochemistry at baseline (Day 0) and at surgery (Day 14-18)*
3. Changes in circulating steroidogenic hormones are measured by analysis of blood samples at baseline and surgery (Day 14-18)
4. Pharmacokinetics of tamoxifen and N-desymethyltamoxifen (DMT) will be measured by mass spectrometry at Mid-treatment (Day 7) and surgery (Day 14-18)
5. Safety and tolerability of progesterone plus tamoxifen will be measured by the following –
5.1. Occurrence of grade 3+toxicity as classified by NCI-CTCAE v4.03 throughout the treatment period until 28 days post treatment.
5.2. Occurrence of adverse events throughout the treatment period until 28 days post treatment.
5.3. Occurrence of withdrawal from trial treatment due to toxicity throughout the treatment period until 28 days post treatment.
5.4. Experience of delay to scheduled surgery.

Overall trial start date

23/01/2017

Overall trial end date

23/06/2019

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Women 16-49 years of age
2. Newly diagnosed histologically confirmed breast cancer
3. Premenopausal as defined by: gonadotrophin levels (luteinizing hormone and follicle stimulating hormone) and estradiol levels within the local laboratory’s reference range for premenopausal females
4. Ability to provide menstrual cycle information
5. ER positive (Allred ≥3)
6. PgR positive (Allred ≥3)
7. HER2 negative (IHC 1+ or 2+ and HER2/CEP17 ratio of <2)
8. Tumour measuring ≥14mm in longest diameter by ultrasound (US)/mammogram examination
9. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
10. Adequate bone marrow function defined by Hb≥10 g/dl, WBC≥3.0 x109 , PLT≥100 x109 /L.
11. Adequate renal function defined by a serum creatinine ≤1.5 x ULN. Adequate liver function defined by total bilirubin ≤ 1.5 ULN (patients with Gilbert’s syndrome exempted), either ALT or AST ≤1.5 ULN and ALP ≤1.5 ULN
12. Written informed consent, able to comply with treatment and follow-up
13. Currently using adequate contraception, and willing to continue use of this for the duration of the trial. Also willing to use a form of adequate contraception for one year following end of treatment (the type of contraception can be changed following the end of the trial). Adequate contraception is defined as either:
13.1. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic absence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
13.2. Sterlisation: have had surgical tubal ligation at least six weeks before taking study treatment.
13.3. Male partner sterilization (with the appropriate postvasectomy documentation of the absence of sperm in the ejaculate). For female study subjects, the vasectomized male partner should be the sole partner for that patient.
13.4. Placement of a copper intrauterine device (IUD)
13.5. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Note: Hormonal contraceptive methods (e.g. oral, injected and implanted) are not permitted.

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 112; UK Sample Size: 112

Participant exclusion criteria

1. Inoperable breast cancer
2. Inflammatory tumours
3. Evidence of metastatic disease
4. Prior endocrine therapy or chemotherapy for breast cancer
5. Any history of invasive malignancy within 5 years of starting study treatment (other than adequately treated basal cell carcinoma or squamous cell carcinoma of the skin and cervical carcinoma in situ)
6. Concomitant use (defined as use within 12 weeks prior to entry) of OCP or any other oestrogen-containing medication or supplement
7. Concomitant use of any of the prohibited medications listed in Section 9.6.2
8. History of thromboembolic disease
9. Known carrier of genetic defects predisposing to thromboembolic disorders
10. Any medical condition that would prevent the use of low molecular weight heparin for venous thromboembolism prophylaxis
11. Uncontrolled abnormalities of serum potassium, sodium, calcium or magnesium levels
12. Evidence of bleeding diathesis
13. Evidence of uncontrolled active infection
14. Evidence of significant medical condition or laboratory finding which, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial
15. Pregnant or lactating women

Recruitment start date

18/06/2018

Recruitment end date

23/12/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Royal Liverpool and Broadgreen University Hospitals NHS Trust Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

Wythenshawe Hospital
University Hospital of South Manchester NHS Foundation Trust Southmoor Road Wythenshaw
Manchester
M23 9LT
United Kingdom

Trial participating centre

New Cross Hospital
The Royal Wolverhampton NHS Trust Wolverhampton Road Heath Town West Midlands
Wolverhampton
WV10 0QP
United Kingdom

Trial participating centre

Arrowe Park Hospital
Wirral University Teaching Hospital NHS Foundation Trust Arrowe Park Road Wirral Merseyide
Upton
CH49 5PE
United Kingdom

Trial participating centre

Macclesfield Distrcit General Hospital
East Cheshire NHS Trust Victoria Road Cheshire
Macclesfield
SK10 3BL
United Kingdom

Trial participating centre

North Manchester General Hospital
Pennine Acute Hospitals NHS Trust Delaunays Road Crumpsall
Manchester
M8 5RB
United Kingdom

Trial participating centre

North Manchester General Hospital
Pennine Acute Hospitals NHS Trust Delaunays Road Crumpsall
Manchester
M8 5RB
United Kingdom

Trial participating centre

Guy’s Hospital
Guy’s and St Thomas’ NHS Foundation Trust Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

The Countess of Chester Health Park
Countess of Chester Hospital Foundation Trust Cheshire
Chester
CH2 1UL
United Kingdom

Trial participating centre

The Royal Bolton Hospital
Bolton NHS Foundation Trust Minerva Road Farnworth Lancashire
Bolton
BL4 0JR
United Kingdom

Trial participating centre

St James’s University Hospital
Derby Teaching Hospitals NHS Foundation Trust Beckett Street West Yorkshire
Leeds
LS9 7TF
United Kingdom

Sponsor information

Organisation

University of Liverpool

Sponsor details

-
Liverpool
L69 3BX
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The main trial results will be published in the name of the trial in a peer-reviewed journal, on behalf of all collaborators.

IPD sharing statement:
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

23/06/2020

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

07/06/2018: The recruitment start date was changed from 23/10/2017 to 18/06/2018. 06/06/2018: Internal review. 14/05/2018: Internal review. 16/01/2018: Internal review. 26/10/2017: Internal review.