Rivaroxaban compared to no treatment in ER-negative stage I-III early breast cancer patients (the TIP Trial): study protocol for a phase II preoperative window-of-opportunity study design randomised controlled trial
Bundred, Nigel J
Harvey, J. R.
Kirwan, Cliona C
AffiliationManchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ, UK.
MetadataShow full item record
AbstractBackground: Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto�, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients. Methods: This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-na�ve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18-36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation. Discussion: Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer. Trial registration: UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .
CitationCastle J, Blower E, Bundred NJ, Harvey JR, Thachil J, Marshall A, et al. Rivaroxaban compared to no treatment in ER-negative stage I�III early breast cancer patients (the TIP Trial): study protocol for a phase II preoperative window-of-opportunity study design randomised controlled trial. Trials. 2020;21(1):749.
- PO-36 - Thrombin Inhibition Preoperatively (TIP) in early breast cancer, the first clinical trial of NOACs as an anti-cancer agent: trial methodology.
- Authors: Kirwan CC, Bundred NJ, Castle J, Clarke R, Dive C, Morris J, Holcombe C, Harvey JR
- Issue date: 2016 Apr
- Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data.
- Authors: Kushnir M, Choi Y, Eisenberg R, Rao D, Tolu S, Gao J, Mowrey W, Billett HH
- Issue date: 2019 Jul
- The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice.
- Authors: Buijs JT, Laghmani EH, van den Akker RFP, Tieken C, Vletter EM, van der Molen KM, Crooijmans JJ, Kroone C, Le Dévédec SE, van der Pluijm G, Versteeg HH
- Issue date: 2019 Jun
- Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.
- Authors: Cohen H, Doré CJ, Clawson S, Hunt BJ, Isenberg D, Khamashta M, Muirhead N, RAPS Trial Protocol Collaborators.
- Issue date: 2015 Sep
- The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications.
- Authors: Raskob GE, Spyropoulos AC, Zrubek J, Ageno W, Albers G, Elliott CG, Halperin J, Haskell L, Hiatt WR, Maynard GA, Peters G, Spiro T, Steg PG, Suh EY, Weitz JI
- Issue date: 2016 Jun 2