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TIP   

Title

Thrombin Inhibition Preoperatively in Early Breast Cancer


Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Recruitment
II Non-CTIMP Open 18 and over University of South Manchester Eudract No: 2014-004909-33
Isrctn No:
8

Purpose

• 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).


Trial Lead Organisations

University of South Manchester / LCTU / NWSTC


Trial Start Date

26/04/2016


Trial Coordinator

Greg Gibson


Trial Coordinator Email Address

greg1@liv.ac.uk


Trial Coordinator Contact No

0151 795 5289


Website Treatment  

The treatment group will be randomized 1:1 between:

  • 10mg Rivaroxaban od.
  • 20mg Rivaroxaban od

 

Rivaroxaban will be administered orally for a minimum of 11 days and maximum of 17 days, but not within 24 hours of surgery102.

 

Following surgery, all patients will be followed up for 2 weeks

Trial Endpoints  


Primary Outcome  

Primary:

  • 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).

 

 


Secondary Outcomes  

Secondary:

In patients receiving preoperative Rivaroxaban, to determine (in post treatment compared to pre-treatment patient samples) if:

  • Mammosphere Forming Efficiency (MFE) of cultured patient tumour tissue is inhibited
  • Tumour tissue demonstrates a reduction in expression of thrombin pathway related markers [Tissue Factor (TF), thrombin-antithrombin (TAT) and Protease Activated Receptor (PAR 1)]
  • Tumour tissue demonstrates an increase in the apoptotic markers, cleaved Caspase 3 expression and TUNEL
  • Tumour demonstrates an increase in the cell cycle inhibitor p27
  • Tumour tissue demonstrates a reduction in the angiogenic marker CD31
  • Circulating tumour cell (CTC) numbers decrease
  • Circulating free DNA (cfDNA) is increased and cfDNA Integrity (cfDI) is decreased
  • Plasma d-dimer, TF and TAT decrease
  • Identification of proteomic biomarkers of response

 

To determine if there is a dose-response to Rivaroxaban in the above measures.

All the above markers will be compared in pre-treatment compared to post-treatment samples, and in post treatment Rivaroxaban compared to placebo arms. In addition, the Rivaroxaban subgroup (divided 1:1 to 20mg once daily [od] or 10mg Rivaroxaban od) will have within-group assessment of dose response using the above markers.

Changes in markers of proliferation (Ki67 and p27), apoptosis (cleaved Caspase 3, TUNEL), angiogenesis (CD31), cfDNA, cfDI, proteomics and changes in MFE and CTC numbers will be correlated to tumour and systemic thrombin pathway activation (tissue TF, TAT, PAR1 and plasma d-dimer, TF and TAT respectively).

To determine if Ki67 score on Tissue MicroArray (TMA) constructs correlation with whole section Ki67 score.

To determine if Ki67 score on TMA constructs determined manually correlates with automated Ki67 score

Eligibility  

Inclusion Criteria

  1. Provision of written informed consent.
  2. World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks
  3. Patients must be able to swallow and retain oral medication
  4. Female patients, age over 18, with histological confirmation of ER negative  invasive breast carcinoma
  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 (free-hand or under ultrasound guidance as per local protocols).
  8. As judged by the 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). Screening for chronic conditions is not required.
  9. Full blood count, renal and liver biochemistry within 10% of laboratory normal limits
  10. Estimated Glomerular Filtration Rate (eGFR) above 50

 

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 or HIV protease inhibitors), dronedarone and strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort
  5. Major surgery within 4 weeks before the first dose of study treatment.
  6. Conditions associated with an increased risk of bleeding:
    1. Major surgery or trauma within the previous month
    2. Hemorrhagic disorder or bleeding diathesis
    3. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding
    4. Gastrointestinal hemorrhage within the past year
    5. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days
    6. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm
    7. Need for anticoagulant treatment of disorders other than atrial fibrillation
    8. Fibrinolytic agents within 48 hours of study entry
    9. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg
  7. Participation in another interventional trial

UK: ENGLAND

  • , Macclesfield District General (Jalal Kokan)
  • , Royal Bolton Hospital (Angela Volleamere)
  • , Royal Liverpool University Hospital (Chris Holcombe)
  • , Wythenshawe Hospital (Manchester) (Cliona Kirwan)

UK: ENGLAND

  • , Arrowe Park Hospital (Wirral) (Raman Vinayagam)
  • , Liverpool Cancer Trials Unit (Chris Holcombe)
  • , North Manchester General Hospital (Maria Bramley)