Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Neoplasm, Venous Thromboembolism

Intervention / Treatment
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* Drug: rivaroxaban
* Drug: Low-molecular-weight heparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low-molecular-weight heparin<br>dalteparin, 200 IU/kg subcutaneously once daily for one month followed by 150 IU/kg subcutaneously once daily for 2 months | Drug: Low-molecular-weight heparin<br>* dalteparin, 200 IU/kg OD for 4 weeks followed by 150 IU/kg OD for 8 weeks<br>* Other names: dalteparin;|
| Experimental: Rivaroxaban<br>rivaroxaban, orally, 15 mg twice daily for 3 weeks followed by 20 mg once daily for 9 weeks | Drug: rivaroxaban<br>* rivaroxaban, 15 mg BD (Bis in die) for 3 weeks followed by 20mg OD (Omni die) for 9 weeks<br>* Other names: xarelto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic DVT | Recurrent VTE during the 3-month treatment period including all symptomatic DVT (lower limbs distal and proximal DVTs, iliac and caval thrombosis, visceral thrombosis and deep vein thrombosis of the arm) | 3 months | 
| Symptomatic PE | Recurrent VTE during the 3-month treatment period including symptomatic PE | 3 months | 
| Unsuspected PE and DVT | Recurrent VTE during the 3-month treatment period including clinically unsuspected PE and DVT discovered incidentally | 3 months | 
| Worsening of pulmonary vascular or venous obstruction | Recurrent VTE during the 3-month treatment period including worsening of pulmonary vascular obstruction or venous obstruction on the systematic examinations performed at the end of the 3-month treatment period | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major and clinically significant bleedings during the 3-month treatment period | Major bleeding is defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and includes any bleeding resulting in death; symptomatic bleeding in a critical organ including intracranial, intra spinal, intraocular, retroperitoneal, intra articular and pericardial bleeding and muscle bleeding resulting in compartment syndrome; symptomatic bleeding resulting in a decrease in the hemoglobin concentration of at least 2g/dL or resulting in the transfusion of at least two packs of blood red cells. | 3 months | 
| Symptomatic recurrences of PE or DVT of the legs | excluding visceral thrombosis, upper extremity deep vein thrombosis and clinically unsuspected PE and DVT diagnosed incidentally | 3 months | 
| Major and non-major clinically significant bleedings at day 90 | Clinically significant non-major bleedings are defined as any bleeding requiring hospitalization or a medical intervention including temporary withholding of anticoagulant treatment to stop bleeding. | 3 months | 
| Mortality |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, venous thromboembolism, low-molecular weight heparin, rivaroxaban