Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban

Efficacy and Safety of Oral Rivaroxaban for the Treatment of Venous Thromboembolism in Patients With Active Cancer. A Pilot Study.

The study will compare the efficacy and safety of oral rivaroxaban and subcutaneous dalteparin in patients with cancer associated thrombosis. It is designed as a non-inferiority open label randomized multicenter trial with blinded adjudication of outcome events.

Patients with active cancer and symptomatic pulmonary embolism, proximal deep vein thrombosis, iliac or caval thrombosis will be randomly assigned to receive either dalteparin using the CLOT regimen or to oral rivaroxaban using the conventional dosage given in the Einstein studies. Experimental and control treatments will be given for three months. The main outcome at three month will include all symptomatic and incidentally discovered venous thromboembolic events including pulmonary embolism (either objectively confirmed and death due to pulmonary embolism), lower limb and upper limb deep vein thrombosis, iliac, caval and visceral thrombosis and any worsening of vascular obstruction which will be collected systematically at inclusion and at day 90. The safety end-points will consist of the rate of major bleedings and the composite of major and non-major but clinically significant bleedings at day 90. All outcome events will be blindly adjudicated by a central independent adjudication committee.

Inclusion Criteria:

• Age > 18 years
• Social security affiliation
• Written informed consent
• Solid active cancer, high grade lymphoma or myeloma treated with Immunomodulatory drugs (IMiDs) (thalidomide or lenalidomide). Active cancer is defined as the presence of measurable disease or ongoing (or planned) chemotherapy, radiotherapy or targeted therapy at inclusion.
• Histologically or cytologically proven cancer.
• Symptomatic venous thromboembolism objectively confirmed diagnosed because of symptoms or discovered incidentally
• High-risk of recurrent Venous thromboembolism (VTE) defined by a score of 0 or ≥ 1, using the following criteria: female sex (+1), lung cancer (+1), breast cancer (-1) non metastatic tumor (-2), previous VTE (+1).

Exclusion Criteria:

• Exclusive adjuvant hormonal treatment with no measurable residual disease
• Sub-segmental isolated pulmonary embolism (PE) without associated proximal DVT
• Isolated distal deep vein thrombosis (DVT) of the legs
• Isolated upper-extremity DVT or superior vena cava thrombosis
• Isolated visceral thrombosis
• Platelet count < 50 000 G/L
• Active bleeding
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
• Hemostatic defect with contraindication to anticoagulant treatment at therapeutic dosage
• Vena cava filter at inclusion
• Fibrinolytic therapy within 3 days preceding inclusion
• Creatinine clearance < 30 ml/min according to Cockcroft-Gault formula
• Previous heparin-induced thrombocytopenia
• Anticoagulant treatment at curative dosage for more than 3 days before inclusion
• Pregnancy or lack of effective contraceptive treatment for women of childbearing age
• Treatment with both strong CYP3A4 and P-glycoprotein (PgP) inhibitors: protease inhibitors for HIV disease, systemic ketoconazole
• Treatment with a strong CYP3A4 inducer: rifampicin, carbamazepine, phenytoin.
• Life expectancy < 3 months
• Eastern Cooperative Oncology Group (ECOG) level 3 or 4