Condition category
Cancer
Date applied
05/11/2015
Date assigned
05/11/2015
Last edited
24/08/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Public

Primary contact

Mr Binyam Tesfaye

ORCID ID

Contact details

Cancer Research UK Liverpool Cancer Trials Unit
University of Liverpool
1st floor Block C
Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
+44 151 7948245
tiptrial@liverpool.ac.uk

Additional identifiers

EudraCT number

2014-004909-33

ClinicalTrials.gov number

Protocol/serial number

19731

Study information

Scientific title

Thrombin Inhibition Preoperatively in early breast cancer (TIP study)

Acronym

TIP

Study hypothesis

The aim of this study is to determine whether preoperative oral Factor Xa inhibitor (Rivaroxaban) in oestrogen receptor negative early breast cancer patients results in inhibition of tumour proliferation markers as determined by a reduction in tumour Ki67 from baseline (pretreatment) to post treatment (at time of surgical excision).

Ethics approval

First Medical Research Ethics Committee, 13/07/2015, ref: 15/NW/0406

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

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

Condition

Topic: Cancer; Subtopic: Breast Cancer; Disease: Breast

Intervention

Patients will be randomised into 3 groups in a 1:1:1 ratio as follows (with the Rivaroxaban treatment groups being combined for primary endpoint analysis creating a 2:1 randomisation for Rivaroxaban vs. no treatment):

Group 1: Preoperative Rivaroxaban 20mg od and excisional approx 14 days later
Group 2: Preoperative Rivaroxaban 10mg od and excisional approx 14 days later
Group 3: No Preoperative therapy with surgery approx 14 days later

Patients should have their surgery booked prior to randomisation and scheduled for around two weeks ahead, as long it is within 31 days from diagnosis. All surgery will be completed to standard care.

Patients will return 2 weeks following the date of surgery for post-op complications and adverse events review. All further follow-up will be as per standard NHS practice with annual clinical and mammographic examination.

Intervention type

Drug

Phase

Not Applicable

Drug names

Rivaroxaban

Primary outcome measures

Percentage reduction in tumour Ki67 expression is measured using tumour core biopsies at baseline (pre-rivaroxaban), surgery (post-rivaroxaban).

Secondary outcome measures

In post Rivaroxaban compared to pre- Rivaroxaban patient samples:
1. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
2. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
3. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
4. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
5. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
6. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
7. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)

In post Rivaroxaban compared to post placebo patient samples:
1. Reduction in MFE is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
5. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
7. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)

In post 20mg od Rivaroxaban compared to post 10mg Rivaroxaban patient samples (subgroup analysis):
1. Reduction in MFE is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
5. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
7. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)

Overall trial start date

26/06/2015

Overall trial end date

01/03/2018

Reason abandoned

Eligibility

Participant inclusion criteria

1. Female patients with histological confirmation of ER negative invasive breast carcinoma
2. Provision of written informed consent.
3. World Health Organisation (WHO) performance status 0-1with no deterioration over the previous 2 weeks
4. Patients must be able to swallow and retain oral medication
5. AJCC Stage 1-3 with primary tumour in the breast amenable to biopsies
6. Scheduled to have definitive breast surgery 11 or more days after study entry
7. Tumour size =10mm (large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy (freehand or under ultrasound guidance as per local protocols).
8. As judged by the site's Principal Investigator, no evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)
9. Full blood count, renal and liver biochemistry (within 10% of laboratory normal limits)
10. EGFR above 50
11. Aged 18 or over

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 81; UK Sample Size: 81; Description: The study is powered on a change in Ki67 from baseline to post treatment. A sample size of 43 patients, in the Rivaroxaban can achieve 90 % power to detect a 0.5 standard deviation (SD) geometric mean Ki67-difference with a two-sided test at the alpha-level of 0.05.

Participant exclusion criteria

1. Tumour size <10mm
2. Prior treatment for breast or other cancer (excluding non-melanoma skin cancer)
3. Concurrent anticoagulant therapy (excluding antiplatelet therapy such as aspirin or clopidogrel)
4. Concurrent treatment with azole-antimycotics (such as, ketoconazole, itraconazole, voriconazole and posaconazole); clarithromycin; HIV protease inhibitors; dronedarone; strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort); strong CYP3A4 or P-gp inhibitors
5. Major surgery within 4 weeks before the first dose of study treatment.
6. Conditions associated with an increased risk of bleeding:
6.1. Major surgery or trauma within the previous month
6.2. Haemorrhagic disorder or bleeding diathesis
6.3. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra‐articular bleeding
6.4. Gastrointestinal haemorrhage within the past year
6.5. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days
6.6. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm
6.7. Need for anticoagulant treatment of disorders other than atrial fibrillation
6.8. Fibrinolytic agents within 48 hours of study entry
6.9. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg
7. Known hypersensitivity or allergy to rivaroxaban and/or excipients
8. Participation in another interventional trial
9. Pregnant or lactating women
10. All women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom for at least two weeks after the end of their treatment

Recruitment start date

01/01/2016

Recruitment end date

01/02/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University Hospital of South Manchester
Wythenshawe Hospital Southmoor Road Wythenshawe
Manchester
M23 9LT
United Kingdom

Trial participating centre

Macclesfield District General Hospital
Victoria Road
Macclesfield
SK10 3BL
United Kingdom

Trial participating centre

North Manchester General Hospital
Delaunays Road
Manchester
M8 5RB
United Kingdom

Trial participating centre

The Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP

Trial participating centre

The Royal Bolton Hospital
Minerva Road Farnworth
Bolton
BL4 0JR
United Kingdom

Sponsor information

Organisation

University Hospital of South Manchester NHS Foundation Trust

Sponsor details

Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The results from different centres will be analysed together and published in a peer reviewed journal.

Intention to publish date

30/06/2018

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

24/08/2016: Cancer Help UK lay summary link added.