Breast Cancer MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Rivaroxaban 20mg
Product Code: N/A
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Rivaroxaban 20mg
CAS Number: 366789-02-8
Concentration unit: mg milligram(s)
Concentration
Sponsors
Manchester University NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Provision of written informed consent. World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks Patients must be able to swallow and retain oral medication Female patients, age over 18, with histological confirmation of ER negative invasive breast carcinoma AJCC Stage 1 - 3 with primary tumour in the breast amenable to biopsies Scheduled to have definitive breast surgery 11 or more days after study entry 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). 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). Screening for chronic conditions is not required. Full blood count, renal and liver biochemistry (within 10% of laboratory normal limits) EGFR above 50. 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 51 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: Tumour size <10mm Prior treatment for breast or other cancer (excluding non-melanoma skin cancer) Concurrent anticoagulant therapy (excluding antiplatelet therapy such as aspirin or clopidogrel) 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 Major surgery within 4 weeks before the first dose of study treatment. Conditions associated with an increased risk of bleeding: a. Major surgery or trauma within the previous month b. Hemorrhagic disorder or bleeding diathesis c. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding d. Gastrointestinal hemorrhage within the past year e. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days f. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm g. Need for anticoagulant treatment of disorders other than atrial fibrillation h. Fibrinolytic agents within 48 hours of study entry i. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg Participation in another interventional trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Percentage reduction in tumour Ki67 expression in post Rivaroxaban tumour core biopsies compared to pre Rivaroxaban tumour core biopsies;Secondary Objective: In pre-treatment compared to post treatment samples, and in between group analysis (no Rivaroxaban vs 10mg Rivaroxaban vs 20mg Rivaroxaban) : In post Rivaroxaban compared to pre- Rivaroxaban patient samples: • Reduction in tumour tissue expression of TF, TAT and PAR 1 and other procoagulant and stromal activation markers • Reduction in tumour tissue expression of CD31 and other angiogenic markers • Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL and other apoptotic cell death / survival markers • Reduction in Circulating Tumour Cells (CTCs) • Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) • Reduction in plasma d-dimer, TF and TAT and other clotting / cancer activity related markers • Alterations in proteomics, correlating to tumour response All changes in tumour and systemic levels of markers will be analysed as a percentage (pre-post/pre x 100) and an absolute (pre-post) change from baseline. Correlation of cancer effects ;Primary end point(s): Percentage reduction in tumour Ki67 expression in post Rivaroxaban tumour core biopsies compared to pre Rivaroxaban tumour core biopsies;Timepoint(s) of evaluation of this end point: The endpoint will be evaluated following the recruitment of the last patient | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 ;Timepoint(s) of evaluation of this end point: The endpoint will be evaluated following the recruitment of the last patient | — |
Countries
United Kingdom
Contacts
Public ContactGreg Gibson
Cancer Research UK Liverpool Cancer Trials Unit
Outcome results
None listed